Thia-aza compounds with a β-lactam ring

ABSTRACT

2-Penem-3-carboxylic acid compounds of the formula ##STR1## in which R 1  represents hydrogen, an organic radical bonded by a carbon atom to the ring carbon atom or an etherified mercapto group and 
     R 2  represents hydroxy or a radical R 2   A  forming together with the carbonyl grouping --C(═O)-- a protected carboxyl group, 
     1-oxides thereof, as well as salts of such compounds having salt-forming groups, in racemic and optically active form, processes for their preparation, pharmaceutical compositions containing such compounds, and their use as antibiotics, and intermediates and their processes which are useful in the production of the compounds of the formula I.

This is a division of application Ser. No. 353,288 filed on Mar. 1,1982, which in turn is a divisional of application Ser. No. 902,639,filed on May 4, 1978, now U.S. Pat. No. 4,331,676, issued May 25, 1982.

The present invention relates to new bicyclic thia-aza compoundscontaining a β-lactam ring unsubstituted in the 3-position and havingantibiotic properties.

Since the discovery of penicillin, numerous bicyclic thia-aza compoundshaving a β-lactam structure have become known. A survey of earlier worksreveals E. H. Flynn, "Cephalosporins and Penicillins", Academic Press,New York and London, 1972. Very recent developments are described by J.Cs. Jaszberenyi et al., Progr. Med. Chem., Vol. 12, 1975, 395-477, andP. G. Sammes, Chem. Rev. 1976, Vol. 76, No. 1, 113-155. At the symposium"Recent Advances in the Chemistry of β-lactam Antibiotics" from 28th to30th June, 1976, held in Cambridge, England,6-acylamino-2-penem-3-carboxylic acid compounds having an antibioticaction and containing the novel 2-penem ring system were described by R.B. Woodward.

Apart from the usual penam and cephem compounds carrying an acylaminogroup in the 6- or 7-position, such compounds that are unsubstituted inthese positions have also become known, for example3-carboxy-2,2-dimethylpenam (J. P. Clayton, J. Chem. Soc., 1969, 2123)and 3-methyl-4-carboxy-3-cephem (K. Kuhlein, Liebigs Ann., 1974, page369 and D. Bormann, ibid., page 1391). None of these compounds, however,has any substantial antibiotic activity, 2-penem compounds that areunsubstituted in the 6-position are so far unknown.

The problem underlying the present invention is to produce bicyclicthia-aza compounds containing a β-lactam ring that possess the 2-penemring system unsubstituted in the 6-position and that are active againstnormal and against resistant bacteria.

The manufacture according to the invention of the novel compounds andthe new intermediate products required therefor open up new fields inwhich research into other commercially valuable compounds can be carriedout.

The ring system of the compounds of the present invention has theformula ##STR2## and may systematically be called7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene. For the sake of simplicityit is referred to hereinafter as "2-penem", wherein the followingnumbering derived from penam and customary in penicillin chemistry shallbe used: ##STR3##

The 2-penem ring system has an asymmetrically substituted carbon atom inthe 5-position, so that corresponding compounds, according to theCahn-Ingoid-Prelog designation, may occur in the (5R)-, (5S)- or theracemic (5R,S)-configuration.

The subject of the present invention is 2-penem-3-carboxylic acidcompounds of the formula ##STR4## in which R₁ represents hydrogen, anorganic radical bonded by a carbon atom to the ring carbon atom, or anetherified mercapto group, and

R₂ represents hydroxy or a radical R₂ ^(A) forming together with thecarbonyl grouping --C(═O)-- a protected carboxyl group,

1-oxides thereof, as well as salts of such compounds having salt-forminggroups, processes for the manufacture of such compounds, alsopharmaceutical preparations containing compounds of the formula I havingpharmacological properties, and the use of the new compounds either aspharmacologically active substances, preferably in the form ofpharmaceutical preparations, or as intermediate products.

An organic radical R₁ bonded by a carbon atom to the ring carbon atom isprimarily an optionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicalhaving up to 18, preferably up to 10, carbon atoms, especiallyoptionally substituted lower alkyl, optionally functionally modifiedcarboxyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl orphenyl-lower alkyl. Examples of substituents of such radicals areoptionally functionally modified, such as optionally etherified oresterified, hydroxy or mercapto groups, for example hydroxy, loweralkoxy, for example methoxy or ethoxy, lower alkanoyloxy, for exampleacetoxy or propionyloxy, halogen, for example chlorine or bromine, orlower alkylthio, for example methylthio or tert.-butylthio, oroptionally functionally modified carboxyl groups, such as carboxyl,lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl,carbamoyl or cyano; also nitro; or amino optionally mono- ordi-substituted, such as by lower alkyl, for example methyl or ethyl, oroptionally disubstituted by lower alkylene, for example 1,4-butylene or1,5-pentylene, or protected, such as acylated.

A lower alkyl radical R₁ contains, for example, up to 7, especially upto 4, carbon atoms, and is, inter alia, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.-butyl or pentyl. Substituted loweralkyl is, primarily, substituted methyl, or ethyl or propyl that aresubstituted in the 1- or especially in the ω-position, such ashydroxymethyl or hydroxyethyl; lower alkoxymethyl or lower alkoxyethyl,for example methoxymethyl or methoxyethyl; lower alkanoyloxymethyl orlower alkanoyloxyethyl, for example acetoxymethyl, propionyloxymethyl oracetoxyethyl; halomethyl or haloethyl, for example chloromethyl orbromomethyl or chloroethyl or bromoethyl; lower alkylthiomethyl or loweralkylthioethyl, such as methylthiomethyl, tert.-butylthiomethyl,methylthioethyl or methylthiopropyl; lower alkoxycarbonylmethyl or loweralkoxycarbonylethyl, for example methoxycarbonylmethyl,ethoxycarbonylmethyl or methoxycarbonylethyl; cyanomethyl or cyanoethyl;or aminomethyl, aminoethyl or aminopropyl that are optionally protected,for example by a semi-ester of carbonic acid, such as bytert.-butoxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, oracylated, such as by optionally substituted acetyl, for examplephenoxyacetyl.

An optionally functionally modified carboxyl group R₁ is a free carboxylgroup or one of the for example esterified or amidated carboxyl groupsmentioned under the groups --C(═O)--R₂ ^(A), such as loweralkoxycarbonyl, for example methoxy-, ethoxy- or tert.-butoxycarbonyl;aryl-lower alkoxycarbonyl, such as benzyloxy-, p-nitrobenzyloxy- ordiphenylmethoxycarbonyl; aryloxycarbonyl, such as phenoxycarbonyloptionally substituted for example by halogen, such as chlorine, bylower alkoxy, such as methoxy, or by nitro, such as phenoxycarbonyl, o-,m- or p-chlorophenoxycarbonyl, pentachlorophenoxycarbonyl, o-, m- orp-methoxyphenoxycarbonyl or p-nitrophenoxycarbonyl; amino-carbonyl oraminocarbonyl mono- or disubstituted by, for example, lower alkyl, forexample methyl or ethyl.

A cycloalkyl radical R₁ has, for example, 3 to 7 carbon atoms and is,for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, whereasa cycloalkyl-lower alkyl radical R₁ contains, for example, 4 to 7 carbonatoms and is, for example, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl or cyclohexylmethyl.

A phenyl or naphthyl radical R₁, for example a 1- or 2-naphthyl radical,or a phenyl-lower alkyl radical R₁, for example a benzyl or 1- or2-phenylethyl radical, may be substituted, preferably in the aromaticradical, for example by lower alkyl such as methyl or ethyl, by loweralkoxy, such as methoxy, or by halogen, such as fluorine or chlorine,further by nitro, amino or substituted amino, such as di-loweralkylamino, for example dimethylamino.

The radical R₁ may alternatively be a heterocyclic orheterocyclic-aliphatic radical, preferably of aromatic character, bondedby a carbon atom, for example such a radical having 5 or 6 ring membersand nitrogen, oxygen or sulphur as hetero atoms, such as pyridyl, forexample 2-, 3- or 4-pyridyl, thienyl, for example 2-thienyl, or furyl,for example 2-furyl, or a corresponding pyridyl-, thienyl- orfuryl-lower alkyl, especially -methyl, radical.

An etherified mercapto group R₁ is etherified by an optionallysubstituted aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aromaticor araliphatic hydrocarbon radical having up to 18, preferably up to 10,carbon atoms, and is especially optionally substituted lower alkylthio,lower alkenylthio, cycloalkylthio, cycloalkyl-lower alkylthio,phenylthio or phenyllower alkylthio. Substituents of such radicals are,for example, optionally functionally modified, such as optionallyetherified or esterified, hydroxy or mercapto, for example hydroxy,lower alkoxy, for example methoxy or ethoxy, lower alkanoyloxy, forexample acetoxy or propionyloxy, halogen, for example chlorine orbromine, or lower alkylthio, for example methylthio; or optionallyfunctionally modified carboxyl groups, such as carboxyl, loweralkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, carbamoylor cyano; also nitro; or amino optionally mono- or di-substituted suchas by lower alkyl, for example methyl or ethyl, or by acyl, such aslower alkanoyl, for example acetyl; or amino optionally di-substitutedby lower alkylene, for example by 1,4-butylene or 1,5-pentylene.

A lower alkylthio radical R₁ contains up to 7, especially up to 4,carbon atoms, and is, for example, methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, tert.-butylthio or pentylthio.Substituted lower alkylthio R₁ is, primarily, substituted methylthio,ethylthio or propylthio, the substituents standing in the 1-, 2- or3-position, such as methoxymethylthio, ethoxymethylthio,methoxyethylthio or methoxypropylthio; lower alkanoyloxymethylthio,lower alkanoyloxyethylthio or lower alkanoyloxypropylthio, such asacetoxymethylthio, acetoxyethylthio or acetoxypropylthio;halomethylthio, haloethylthio or halopropylthio, for examplechloroethylthio or bromoethylthio, or chloropropylthio orbromopropylthio; lower alkoxycarbonylmethylthio or loweralkoxycarbonylethylthio, for example methoxycarbonylethylthio;cyanomethylthio; cyanoethylthio; or optionally protected, for exampleacetylated, aminomethylthio, aminoethylthio or aminopropylthio.

A lower alkenylthio radical R₁ contains 2 to 7, especially 2 to 4,carbon atoms and is especially 1-lower alkenylthio, for example,vinylthio, 1-propenylthio, 1-butenylthio or 1-pentenylthio or also2-lower alkenylthio, for example allylthio. Substituted loweralkenylthio R₁ is, primarily, substituted in the 2-position, wherein thesubstituents that chiefly come into consideration are lower alkoxy,lower alkanoyloxy and optionally protected amino. Thus R₁ is, forexample, 2-methoxyvinylthio, 2-acetoxyvinylthio, 2-acetylaminovinylthioor correspondingly substituted 1-propenylthio.

A cycloalkylthio group R₁ has, for example, 3 to 7 carbons atoms, andis, for example, cyclopropylthio, cyclobutylthio, cyclopentylthio orcyclohexylthio.

A cycloalkyl-lower alkylthio radical R₁ has, for example, 4 to 7 carbonatoms and is, for example, cyclopropylmethylthio, cyclobutylmethylthio,cyclopentylmethylthio or cyclohexylmethylthio.

A phenylthio radical R₁ or a phenyl-lower alkylthio radical R₁, forexample benzyl- or 1- or 2-phenylethylthio radical, may be substituted,preferably in the aromatic radical, for example by lower alkyl, such asmethyl or ethyl, by lower alkoxy, such as methoxy, by halogen, such asfluorine or chlorine, or by nitro or amino.

A protected carboxyl group of the formula --C(═O)--R₂ ^(A) is primarilyan esterified carboxyl group in which R₂ ^(A) represents a hydroxy groupetherified by an organic radical or an organic silyl or stannyl group.Organic radicals, also as substituents in organic silyl or stannylgroups, are aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic radicals, especially optionally substitutedhydrocarbon radicals of this type, and heterocyclic orheterocyclic-aliphatic radicals, preferably having up to 18 carbonatoms.

An etherified hydroxy group R₂ ^(A) forms together with the carbonylgrouping an esterified carboxyl group that can preferably be readilysplit, for example by reduction, such as by hydrogenolysis, or bysolvolysis, such as acid hydrolysis or, especially, basic or neutralhydrolysis, oxidatively, or under physiological conditions, or anesterified carboxyl group that is readily convertible into anotherfunctionally modified carboxyl group, such as into another esterifiedcarboxyl group or into a hydrazinocarbonyl group. Such a group R₂ ^(A)is, for example, 2-halo-lower alkoxy, in which the halogen preferablyhas an atomic weight of more than 19, for example 2,2,2-trichloroethoxyor 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy which may readilybe converted into the latter, or 2-lower alkylsulphonyl-lower alkoxy,for example, 2-methylsulphonylethoxy. The group R₂ ^(A) is furthermore amethoxy group polysubstituted by optionally substituted hydrocarbonradicals, especially saturated aliphatic or aromatic hydrocarbonradicals, such as lower alkyl, for example methyl, and/or phenyl, or isa methoxy group monosubstituted by an unsaturated aliphatic hydrocarbonradical, such as lower alkenyl, for example 1-lower alkenyl, such asvinyl, by a carbocyclic aryl group having electron-donatingsubstituents, or by a heterocyclic group of aromatic character havingoxygen or sulphur as ring member. Examples of such groups R₂ ^(A) aretert.-lower alkoxy, for example tert.-butoxy or tert.-pentoxy;optionally substituted diphenylmethoxy, for example diphenylmethoxy or4,4'-dimethoxydiphenylmethoxy; lower alkenyloxy, especially 2-loweralkenyloxy, for example allyloxy; lower alkoxyphenyl-lower alkoxy, forexample lower alkoxybenzyloxy, such as methoxybenzyloxy (in whichmethoxy is, primarily, in the 3-, 4- and/or 5-position), primarily 3- or4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy; or, above all,nitrobenzyloxy, for example, 4-nitrobenzyloxy, 2-nitrobenzyloxy or4,5-dimethoxy-2-nitrobenzyloxy; or furfuryloxy, such as 2-furfuryloxy.The group R₂ ^(A) is furthermore a 2-oxoethoxy group that is optionallysubstituted in the 2-position by lower alkyl, such as methyl, by loweralkoxy, such as methoxy or ethoxy, by aralkyl, such as benzyl, or byaryl, such as phenyl, and is optionally substituted in the 1-position bylower alkyl, such as methyl, lower alkoxycarbonyl, such asmethoxycarbonyl, lower alkylcarbonyl, such as methylcarbonyl,aralkylcarbonyl, such as benzylcarbonyl, or arylcarbonyl, such asbenzoyl. Thus R₂ ^(A) represents, for example, acetonyloxy, phenacyloxy,2,4-dioxo-3-pentoxy, 1-methoxycarbonyl-2-oxopropoxy or1-ethoxycarbonyl-2-oxopropoxy. The group R₂ ^(A) is alternatively a2-cyanoethoxy group that is optionally substituted in the 1- and/or inthe 2-position, for example by lower alkyl, such as methyl, or by aryl,such as optionally substituted phenyl, and represents, for example,2-cyanoethoxy or 2-cyano-2-phenylethoxy. R₂ ^(A) is alternatively a2-(S₁)(S₂)(S₃)-silylethoxy group, in which each of the substituents S₁,S₂ and S₃ independently of one another represents an optionallysubstituted hydrocarbon radical and the individual radicals may belinked by a single C--C bond. A hydrocarbon radical S₁, S₂, S₃ is, forexample, an alkyl radical, a cycloalkyl radical or an aryl radical,preferably such a radical having a maximum of 12 carbon atoms, whereinthe radical of one kind may be substituted by a radical of a differentkind, or by lower alkoxy, such as methoxy, or by halogen, such asfluorine or chlorine; and is especially lower alkyl having up to 7,preferably up to 4, carbon atoms, such as methyl, ethyl, propyl orbutyl; cycloalkyl having up to 7 carbon atoms, such as cyclopropyl orcyclohexyl; cycloalkylalkyl, such as cyclopentylmethyl; aryl having upto 10 carbon atoms, such as phenyl, tolyl or xylyl; or aryl-lower alkyl,such as benzyl or phenylethyl. Radicals R₂ ^(A) of this kind to besingled out are 2-tri-lower alkylsilylethoxy, such as2-trimethylsilylethoxy or 2-(dibutylmethylsilyl)-ethoxy, and2-triarylsilylethoxy, such as 2-triphenylsilylethoxy.

R₂ ^(A) may alternatively be 2-oxa- or 2-thia-cycloalkoxy or-cycloalkenyloxy having 5-7 ring members, such as 2-tetrahydrofuryloxy,2-tetrahydropyranyloxy or 2,3-dihydro-2-pyranyloxy or a correspondingthia group, or R₂ ^(A) forms together with the --C(═O)-- grouping anactivated ester group and is, for example, nitrophenoxy, for example4-nitrophenoxy or 2,4-dinitrophenoxy, or polyhalophenoxy, for examplepentachlorophenoxy. R₂ ^(A) may, however, alternatively be an unbranchedlower alkoxy, for example methoxy or ethoxy.

An organic sityloxy or organic stannyloxy group R₂ ^(A) is especially asilyloxy or stannyloxy group substituted by 1 to 3 optionallysubstituted hydrocarbon radicals, preferably having up to 18 carbonatoms. It contains as substituents preferably optionally substituted,for example by lower alkoxy, such as methoxy, or by halogen, such aschlorine, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbonradicals, such as lower alkyl, halogen-lower alkyl, cycloalkyl, phenylor phenyllower alkyl and represents primarily tri-lower alkylsilyloxy,for example, trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyloxy,for example, chloromethoxymethylsilyloxy, or tri-lower alkylstannyloxy,for example tri-n-butylstannyloxy.

The group R₂ ^(A) may alternatively be an etherified hydroxy group thattogether with the carbonyl grouping --C(═O)-- forms an esterifiedcarboxyl group that can be split under physiological conditions,primarily an acyloxymethoxy group, in which acyl represents, forexample, the radical of an organic carboxylic acid, primarily anoptionally substituted lower alkanecarboxylic acid, or in whichacyloxymethyl forms the radical of a lactone. Hydroxy groups etherifiedin this manner are lower alkanoyloxymethoxy, for example acetoxymethoxyor pivaloyloxymethoxy; amino-lower alkanoyloxymethoxy, especiallyα-amino-lower alkanoyloxymethyl, for example glycyloxymethoxy,L-valyloxymethoxy, L-leucyloxymethoxy, and also phthalidyloxy. In otherester groups --C(═O)--R₂ ^(A) that can be physiologically split, R₂ ^(A)is a 2-aminoethoxy group, in which amino is substituted by two loweralkyl groups or by alkylene optionally containing an oxa group, andrepresents, for example 2-dimethylaminoethoxy, 2-diethylaminoethoxy or2-(1-morpholino)-ethoxy.

A radical R₂ ^(A) forming with a --C(═)--grouping an optionallysubstituted hydrazinocarbonyl group is, for example, hydrazino or2-lower alkylhydrazino, for example 2-methylhydrazino.

Preferred groups R₂ ^(A) are those that can be converted into a freehydroxy group under neutral, basic or physiological conditions.

Salts are especially those of compounds of the formula I with an acidgrouping such as a carboxyl group, primarily metal or ammonium salts,such as alkali metal and alkaline earth metal salts, for example sodium,potassium, magnesium or calcium salts; as well as ammonium salts withammonia or suitable organic amines, primarily aliphatic, cycloaliphatic,cycloaliphaticaliphatic or araliphatic primary, secondary or tertiarymono-, di- or polyamines, or heterocyclic bases, such as loweralkylamines, for example triethylamine; hydroxy-lower alkylamines, forexample 2-hydroxyethylamine, di-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine; basic aliphatic esters of carboxylic acids,for example 4-aminobenzoic acid 2-diethylaminoethyl ester; loweralkyleneamines, for example 1-ethylpiperidine; cycloalkylamines, forexample bicyclohexylamine; or benzylamines, for exampleN,N'-dibenzylethylenediamine; and also, bases of the pyridine type, forexample pyridine, collidine or quinoline. Compounds of the formula Ithat have basic group may likewise form acid addition salts, for examplewith inorganic acids, such as hydrochloric acid, sulphuric acid orphosphoric acid, or with suitable organic carboxylic or sulphonic acids,for example trifluoroacetic acid or p-toluenesulphonic acid. Compoundsof the formula I having an acid and a basic group may also occur in theform of inner salts, that is in the zwitterion form. 1-oxides ofcompounds of the formula I having salt-forming groups may likewise formsalts as described above. Salts that can be used pharmaceutically arepreferred.

The penem compounds of the formula I may, on account of the asymmetriccarbon atom in the 5-position, occur in the (5R)-, (5S)- or (5R,S)-configuration. The (5R)-compounds are preferred.

The compounds of the present invention have valuable pharmacologicalproperties or may be used as intermediate products for the manufactureof compounds having such properties. Compounds of the formula I, inwhich R₁ has the meaning given above and R₂ represents hydroxy or anetherified hydroxy group, R₂ ^(A) forming together with the carbonylgroup an esterified carboxyl group that can be readily split preferablyunder physiological conditions, or pharmacologically usable salts ofsuch compounds having salt-forming groups, inhibit, for example, thegrowth of gram-positive and gram-negative bacteria, such asStaphylococcus aureus and penicillin-resistant Staphylococcus aureus,Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa andPseudomonas aeruginosa R.

Using the compounds of the formula I according to the invention in thedisc-plate test with the specified bacteria with a 0.5% strengthsolution on filter paper (6 mm diameter) inhibiting zones ofapproximately 16 to 33 mm diameter are found, whereas Penicillin Vtested analogously at the same time, in the case of normalStaphylococcus aureus bacteria causes inhibiting zones of 31 to 32 mmdiameter and in the case of resistant bacteria inhibiting zones of only10 to 11 mm.

The compounds of the formula I according to the invention are effectivein vitro in the following dosage ranges: against cocci (inclusive ofpenicillinase-formers), from <0.1 to 64 mcg/ml; against entero bacteria(inclusive of β-lactamase-formers), from 0.5 to 128 mcg/ml; and againstPseudomonas aeruginosa, from 2 to 128 mcg/ml. In vivo (mouse) they areeffective with subcutaneous administration against streptococcus in adosage range of from 8 to 50 mg/kg.

Attention is drawn in particular to the activity against Pseudomonasaeruginosa, against which neither Penicillin V nor Penicillin G iseffective.

The compounds inhibit β-lactamase and have a synergistic effect incombination with other β-lactam antibiotics.

These new compounds, especially the preferred ones, or theirpharmacologically usable salts, may therefore be used, for example, inthe form of antibiotically-active preparations, in the treatment ofhuman or animal bodies for corresponding systemic or organ infections,as fodder additives, for preserving foodstuffs or as disinfectants.

1-oxides of compounds of the formula I, in which R₁ and R₂ have themeaning given in connection with formula I, or compounds of the formulaI in which R₁ has the meaning given above and R₂ represents a radical R₂^(A) forming together with the --C(═O)-- grouping a protected carboxylgroup that can preferably be readily split, wherein a carboxyl groupprotected in this manner is different from a carboxyl group that can besplit physiologically, are valuable intermediate products that can beconverted in a simple manner, for example as described below, into theabove-mentioned, pharmacologically active compounds.

The invention relates especially to the 2-penem compounds of the formulaI, in which R₁ represents hydrogen; a lower alkyl optionally substitutedby etherified or esterified hydroxy or mercapto, such as lower alkoxy,lower alkanoyloxy or lower alkylthio, by functionally modified carboxyl,such as lower alkoxycarbonyl, or by optionally substituted, for example,acylated, amino; or represents phenyl-lower alkyl or phenyl optionallysubstituted by lower alkyl, lower alkoxy, halogen, nitro, amino ordi-lower alkylamino; an aromatic heterocyclic radical, or an etherifiedmercapto group, such as lower alkylthio; and R₂ represents hydroxy; ahydroxy group etherified by an organic radical or an organic silyl orstannyl group, that can be split under basic or neutral conditions orphysiologically; or represents an optionally substituted hydrazino groupR₂ ^(A), and relates to salts of such compounds with salt-forminggroups.

In a 2-penem compound of the formula I or in a salt of such a compoundhaving salt-forming groups, R₁ primarily represents hydrogen; loweralkyl having up to 7 carbon atoms, for example methyl, isopropyl orpentyl; lower alkoxy-lower alkyl, in which lower alkyl in each casecontains up to 4 carbon atoms, for example methoxymethyl; loweralkanoyloxy-lower alkyl, in which lower alkyl in each case contains upto 4 carbon atoms, for example acetoxymethyl; lower alkylthio-loweralkyl, in which lower alkyl in each case contains up to 4 carbon atoms,for example methylthiomethyl or tert.-butylthiomethyl; loweralkoxycarbonyl-lower alkyl, in which lower alkyl in each case containsup to 4 carbon atoms, such as lower alkoxycarbonylmethyl or loweralkoxycarbonylethyl, for example methoxycarbonylethyl; amino-loweralkyl, in which lower alkyl contains up to 4 carbon atoms and in whichthe amino group is optionally acylated by a semi-ester of carbonic acidor by a substituted acetyl group, for example aminomethyl, aminoethyl oraminopropyl, or the corresponding aminomethyl, aminoethyl or aminopropylN-acylated by benzyloxycarbonyl, p-nitrobenzyloxycarbonyl orphenoxyacetyl; or phenyl optionally substituted by lower alkyl, halogen,nitro, amino or di-lower alkylamino, for example phenyl ordimethylaminophenyl; phenyl-lower alkyl, for example benzyl; an aromaticheterocyclyl radical containing 5 or 6 ring members with a nitrogen, anoxygen or a sulphur atom as hetero atom, for example pyridyl, furyl orthienyl; or lower alkylthio, for example ethylthio; and R₂ primarilyrepresents hydroxy, or an etherified hydroxy group that can be splitunder basic or neutral conditions or physiologically, such as optionallyα-polybranched lower alkoxy, for example tert.-butyloxy, 2-substituted2-oxoethoxy, for example acetonyloxy, or phenacyloxy, 2-cyanoethoxy,2-(S₁)(S₂)(S₃)-silylethoxy, in which each of S₁, S₂ and S₃ representslower alkyl, such as methyl, or phenyl, such as 2-trimethylsilylethoxyor 2-triphenylsilylethoxy, 1-phenyl-lower alkoxy having 1-3 phenylradicals optionally substituted by lower alkoxy and/or nitro, forexample 4-methoxybenzyloxy, 4-nitrobenzyloxy,2-nitro-4,5-dimethoxybenzyloxy, diphenylmethoxy,4,4'-dimethoxydiphenylmethoxy or trityloxy, lower alkanoyloxymethoxy,for example acetoxymethoxy or pivaloyloxymethoxy, α-amino-loweralkanoyloxymethoxy, for example glycyloxymethoxy, 2-phthalidyloxy,pentachlorophenoxy, also tri-lower alkylsilyloxy, for exampletrimethylsilyloxy, and lower alkenyloxy, especially 2-lower alkenyloxy,for example allyloxy.

The invention relates primarily to 2-penem compounds of the formula I inwhich

R₁ represents hydrogen, lower alkyl having up to 5 carbon atoms, such asmethyl, isopropyl, or pentyl; lower alkoxy-lower alkyl having up to 4carbon atoms, for example, methoxymethyl; or lower alkanoyloxy-loweralkyl having up to 4 carbon atoms, for example, acetoxymethyl; loweralkylthio-lower alkyl having up to 5 carbon atoms, for example,methylthiomethyl or tert.-butylthiomethyl; lower alkoxycarbonyl-loweralkyl having up to 5 carbon atoms, for example 2-methoxycarbonylethyl;amino-lower alkyl such as aminomethyl, 2-aminoethyl or 3-aminopropyl,optionally N-acylated by benzyloxycarbonyl, p-nitrobenzyloxycarbonyl orby phenoxyacetyl; phenyl optionally substituted by dimethylamino;benzyl; pyridyl, for example 2-, 4- or especially 3-pyridyl; furyl, forexample 3-furyl or especially 2-furyl; or thienyl, for example 3- orespecially 2-thienyl; or lower alkylthio having up to 4 carbon atoms,for example, ethylthio; and

R₂ primarily represents hydroxy, the above-mentioned etherified hydroxygroups that can be split under basic or neutral conditions orphysiologically, especially p-nitrobenzyloxy or acetonyloxy,

and to salts, especially pharmacologically usable non-toxic salts, ofsuch compounds having salt-forming groups, such as the alkali metal, forexample sodium, or alkaline earth metal, for example calcium, salts, orammonium salts, inclusive of those with amines, of compounds of theformula I, in which R₂ represents hydroxy.

The invention relates primarily to 2-R₁ -2-penem-3-carboxylic acidcompounds, in which

R₁ represents hydrogen, methyl, pentyl, acetoxymethyl,tert.-butylthiomethyl, 2-methoxycarbonylethyl, 2-aminoethyl,3-aminopropyl, phenoxyacetylaminomethyl,3-(2-phenoxyacetylamino)-propyl, phenyl, 3-dimethylaminophenyl, benzyl,2-furyl, 3-pyridyl or ethylthio,

and to the salts, especially the pharmacologically usable salts of suchcompounds having salt-forming groups.

The new compounds may be produced by ring-closing an ylid compound ofthe formula ##STR5## in which Z represents oxygen or sulphur and

R₁ and R₂ ^(A) have the meanings given above, wherein functional groupsin these radicals are preferably present in the protected form,

and wherein X.sup.⊕ represents either a phosphonio group substitutedthree times, or a phosphono group esterified twice together with acation,

and, if desired or necessary, converting the protected carboxyl group ofthe formula --C(═O)--R₂ ^(A) in a compound of the formula I obtainedinto the free or into a different protected carboxyl group, and/or, ifdesired, converting a compound of the formula I obtained into thecorresponding 1-oxide and, if desired, converting this into a compoundof the formula I, and/or, if desired, within the definition converting acompound of the formula I obtained into a different compound of theformula I, and/or, if desired, converting a compound obtained having asalt-forming group into a salt, or a salt obtained into the freecompound or into a different salt, and/or, if desired, separating amixture of isomeric compounds obtained into the individual isomers.

In the starting material of the formula II, R₁ is especially one of thepreferred, optionally substituted hydrocarbon radicals, whereinfunctional groups are usually present in the protected form, amino, forexample, in acylated form or alternatively in the form of the nitro orazido group.

In a starting material of the formula II, R₂ ^(A) preferably representsan etherified hydroxy group forming together with the --C(═O)-- groupingan esterified carboxyl group that can readily be split, especially undermild conditions, wherein functional groups that are optionally presentin a carboxyl protective group R₂ ^(A) may be protected in a mannerknown per se, for example as indicated above. A group R₂ ^(A) is interalia lower alkoxy, especially α-polybranched lower alkoxy, for examplemethoxy or tert.-butyloxy; lower alkenyloxy, especially 2-loweralkenyloxy, for example allyloxy; or 2-halo-lower alkoxy, for example2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy; 2-loweralkylsulphonyl-lower alkoxy, for example 2-methylsulphonylethoxy; or anoptionally substituted, such as lower alkoxy-, for example methoxy- ornitro-containing, 1-phenyl-lower alkoxy group, such as diphenylmethoxyor benzyloxy optionally substituted, for example as mentioned, forexample benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxyor 4,4'-dimethoxydiphenylmethoxy; pentachlorophenoxy; acetonyloxy;2-cyanoethoxy; a 2-(S₁)(S₂)(S₃)-silylethoxy group, such as2-trimethylsilylethoxy, 2-(dibutylmethylsilyl)-ethoxy or 2-triphenylsilylethoxy; also an organic silyloxy or stannyloxy group,such as tri-lower alkylsilyloxy, for example trimethylsilyloxy; or oneof the mentioned etherified hydroxy groups that can be splitphysiologically.

The group X.sup.⊕ in the starting material of the formula II is one ofthe phosphonio or phosphono groups customary in the Wittig condensationreaction, especially a triaryl-, for example triphenyl-, or tri-loweralkyl-, for example tributylphosphonio group, or a phosphono groupesterified twice by lower alkyl, for example ethyl, wherein the symbolX.sup.⊕ in the case of the phosphono group additionally includes thecation of a strong base, especially a suitable metal, such as alkalimetal, for example a lithium, sodium or potassium, ion. Preferred asgroup X.sup.⊕ is in one case triphenylphosphonio and in the other casediethylphosphono together with an alkali metal ion, for example sodiumion.

In phosphonium compounds of the formula II, which in the isomeric yleneform are alternatively caled phosphorane compounds, the negative chargeis neutralised by the positively charged phosphonio group. In phosphonocompounds of the formula II, which in their isomeric form canalternatively be called phosphonate compounds, the negative charge isneutralised by the cation of a strong base, which cation, depending onthe method of production of the phosphono starting material, may be, forexample, an alkali metal ion, for example, a sodium, lithium orpotassium ion. The phosphonate starting substances are therefore used assalts in the reaction.

Formula II above the starting material in the form in which the ringclosure takes place. Normally the corresponding phosphoranylidenecompound of the formula ##STR6## in which X₁ represents atri-substituted, especially a triaryl-, for example triphenyl-, or atri-lower alkyl-, for example tri-n-butyl-phosphoranylidene radical, orthe corresponding phosphono compound of the formula ##STR7## in which X₂represents a phosphono-, especially a dialkylphosphono-, for example, adiethylphosphono group, is used, wherein a phosphono starting materialof the formula IIB is converted into the form suitable for the ringclosure, that is into the compound of the formula II, by treating with asuitable basic reagent, such as an inorganic base, for example an alkalimetal carbonate, such as sodium or potassium carbonate, or with anorganic base, such as a tri-lower alkylamine, for example triethylamine,or a cyclic base of the amidine type, such as an appropriatediaza-bicycloalkene compound, for example1,5-diaza-bicyclo[5.4.0]undec-5-ene.

Preferred starting materials are the phosphoranylidene compounds of theformula IIA.

The ring closure can take place spontaneously, that is to say during theproduction of the starting materials, or by heating, for example in atemperature range of approximately 30° C. to approximately 160° C.,preferably of approximately 50° C. to approximately 100° C.

The reaction is preferably carried out in the presence of a suitableinert solvent, such as in an aliphatic, cycloaliphatic or aromatichydrocarbon, for example hexane, cyclohexane, benzene or toluene; ahalogenated hydrocarbon, for example methylene chloride; an ether, forexample diethyl ether; a lower alkylene glycol di-lower alkyl ether, forexample dimethoxyethane or diethylene glycol dimethyl ether, or a cyclicether, for example dioxan or tetrahydrofuran; a carboxylic acid amide,for example dimethylformamide; a di-lower alkyl sulphoxide, for exampledimethyl sulphoxide; or a lower alkanol, for example methanol, ethanolor tert.-butanol; or in a mixture thereof, and, if necessary, in aninert gas atmosphere, for example an argon or nitrogen atmosphere. Ifnecessary the reaction can be carried out in the presence of anantioxidant, such as a sterically hindered phenol, for example2,6-di-tert.-butylcresol, or an optionally substituted1,4-dihydroxybenzene, especially hydroquinone.

In a compound of the formula I obtainable according to the inventionhaving a protected, especially an esterified, carboxyl group of theformula --C(═O)--R₂ ^(A), the latter can be converted in a manner knownper se, for example depending on the type of group R₂ ^(A), into thefree carboxyl group. For example, a carboxyl group esterified by asuitable 2-halo-lower alkyl group, an arylcarbonylmethyl group or a4-nitrobenzyl group can be converted into the free carboxyl group forexample by treating with a chemical reducing agent, such as a metal, forexample zinc, or a reducing metal salt, such as a chromium(II) salt, forexample chromium(II) chloride, usually in the presence of ahydrogen-yielding agent, which together with the metal enables thenascent hydrogen to be produced, such as an acid, chiefly acetic orformic acid, or an alcohol, wherein water is preferably added; acarboxyl group esterified by an arylcarbonylmethyl group can beconverted into the free carboxyl group by treating with a nucleophilic,preferably salt-forming reagent, such as sodium thiophenolate or sodiumiodide; and also a carboxyl group esterified by 4-nitrobenzyl can beconverted into the free carboxyl group by treating with an alkali metaldithionite, for example sodium dithionite. A carboxyl group esterifiedby a 2-lower alkylsulphonyl-lower alkyl group can be split and released,for example by treating with a basic agent, for example one of thenucleophilic-reacting bases mentioned further below; a carboxyl groupesterified by a suitable arylmethyl grouping can be split and released,for example by radiation, preferably with ultra-violet light, forexample of less than 290 mμ when the arylmethyl group is, for example, abenzyl radical optionally substituted in the 3-, 4- and/or 5-positionfor example by lower alkoxy and/or nitro groups, or with longer-waveultraviolet light, for example of above 290 mμ when the arylmethyl groupis, for example, a benzyl radical substituted in the 2-position by anitro group; a carboxyl group esterified by a suitably substitutedmethyl group, such as tert.-butyl or diphenylmethyl, can be split andreleased, for example, by treating with a suitable acid medium, such asformic acid or trifluoroacetic acid, optionally with the addition of anucleophilic compound, such as phenol or anisole; and an esterifiedcarboxyl group that can be split by hydrogenolysis, for examplebenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, can be split and releasedby hydrogenolysis, for example by treating with hydrogen in the presenceof a noble metal, for example a palladium, catalyst. In addition, acarbonyl group esterified with a lower alkenyl group, such as with2-lower alkenyl, especially allyl, can be converted oxidatively, forexample by treating with ozone, followed by a reducing agent, forexample dimethyl sulphide, into a formylmethoxycarbonyl group, fromwhich the carboxyl group can be released by treating with a base, suchas a secondary amine, for example dimethylamine; or a 2-loweralkenyloxycarbonyl group, for example allyloxycarbonyl, can beisomerised, for example by treating with tris-triphenylphosphine rhodiumchloride, palladium-on-carbon, or an alkali metal lower alkanolate, forexample tert.-butylate, in dimethyl sulphoxide to form a 1-loweralkenyloxycarbonyl group and this can be split hydrolytically underweakly acidic or weakly basic conditions. A 2-oxoethoxycarbonyl or2-cyanoethoxycarbonyl group optionally substituted in the 2-position bylower alkyl or by aryl, for example the acetonyloxycarbonyl or2-cyanoethoxycarbonyl group, can be converted under mild conditions,that is at room temperature or while cooling, by treatment with asuitable base, into the corresponding salt of this carboxyl group, fromwhich the free carboxyl group can be obtained by acidification. Suitablebases are nucleophilic-reacting metal, such as alkaline earth metal, andespecially alkali metal, bases, such as corresponding hydroxides,carbonates, bicarbonates, alkoxides, phenolates, mercaptides,thiophenolates or amides, for example sodium hydroxide, sodiumcarbonate, sodium bicarbonate, sodium ethanolate, sodium thiophenolate,sodium amide or sodium morpholide, or corresponding lithium or potassiumcompounds, which are used in water in aqueous or hydroxylgroup-containing solvents or alternatively in polar inert solvents withsubsequent treatment with water. To split the 2-cyanoethoxycarbonylgroups, it is also possible to use tertiary amines, such as tri-loweralkylamine, for example triethylamine or Hunig base, or cyclic orbicyclic amines or imines, such as N-methylmorpholine or1,5-diazabicyclo[5,4,0]undec-5-ene, in an inert solvent, such asmethylene chloride or tetrahydrofuran, wherein the correspondingammonium salts of the carboxyl compound are obtained directly. Asubstituted silylethoxycarbonyl group can be converted into the freecarboxyl group by treatment with a salt of hydrofluoric acid that yieldsfluoride anions, such as an alkali metal fluoride, for example sodium orpotassium fluoride, in the presence of a macrocyclic polyether ("Crownether"), or with a fluoride of an organic quaternary base, such astetraalkylammonium fluoride or trialkylarylammonium fluoride, forexample tetraethylammonium fluoride or tetrabutylammonium fluoride, inthe presence of an aprotic polar solvent, such as dimethyl sulphoxide orN,N-dimethylacetamide. A pentachlorophenyloxycarbonyl group can beconverted into a free carboxyl group under mild conditions, for exampleby dilute sodium carbonate solution or sodium bicarbonate solution or byan organic base in the presence of water.

A carboxyl group protected, for example, by silylation or stannylation,can be released in the usual manner by solvolysis for example bytreating with water or an alcohol.

If there is more than one protected carboxyl group present in a compoundobtainable in accordance with the invention, these may be converted intofree carboxyl groups either jointly or selectively.

In a compound of the formula I obtainable in accordance with the processthat contains a free carboxyl group of the formula --C(═O)--OH, such agroup can be converted in a manner known per se into a protectedcarboxyl group. For example, esters are obtained, for example bytreating with a suitable diazo compound, such as a diazo-lower alkane,for example dizomethane or diazobutane, or a phenyldiazo-lower alkane,for example diphenyldiazomethane, if necessary in the presence of aLewis acid, such as, for example, boron trifluoride, or by reacting withan alcohol suitable for esterification in the presence of an esterifyingagent, such as a carbodiimide, for example dicyclohexylcarbodiimide, orcarbonyldiimidazole, or further with an N,N'-disubstituted O- orS-substituted isourea or isothiourea, in which an O- and S-substituentis, for example, lower alkyl, especially tert.-butyl, phenyl-lower alkylor cycloalkyl, and N- or N'-substituents are, for example, lower alkyl,especially isopropyl, cycloalkyl or phenyl, or according to any otherknown and suitable method of esterification, such as reacting a salt ofthe acid with a reactive ester of an alcohol and a strong inorganic acidor strong organic sulphonic acid. Further, acid halides, such as acidchlorides (produced, for example, by treating with oxalyl chloride),activated esters (formed, for example, with an N-hydroxy nitrogencompound, such as N-hydroxysuccinimide) or mixed anhydrides (obtained,for example, with haloformic acid lower alkyl esters, such aschloroformic acid ethyl ester or chloroformic acid isobutyl ester, orwith haloacetic acid halides, such as trichloroacetic acid chloride) canbe converted into an esterified carboxyl group by reacting withalcohols, optionally in the presence of a base, such as pyridine.

In a compound of the formula I having an esterified grouping of theformula --C(═O)--R₂ ^(A), this grouping can be converted into adifferent esterified carboxy group of this formula, for example2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl can be converted into2-iodoethoxycarbonyl by treating with an iodine salt, such as sodiumiodide, in the presence of a suitable solvent, such as acetone.

In a compound having a free carboxyl group of the formula --C(═O)--OHobtainable according to the process, such a group can also be convertedinto an optionally substituted hydrazinocarbonyl group, by reactingpreferably reactive functionally modified derivatives such as theabove-mentioned acid halides, generally esters such as theabove-mentioned activated esters, or mixed anhydrides of thecorresponding acid with hydrazines.

A carboxyl group protected by an organic silyl or stannyl group can beformed in a manner known per se, for example by treating compounds ofthe formula I in which R₂ represents hydroxy, or salts, such as alkalimetal salts, for example sodium salts, thereof, with a suitablesilylation or stannylation agent, such as one of the above-mentionedsilylation or stannylation agents.

In the process according to the invention, and in additional steps to becarried out where applicable and where necessary, if required freefunctional groups that do not participate in the reaction aretransiently protected in a manner known per se; for example, free aminogroups are transiently protected, for example by acylation, tritylationor silylation; free hydroxy groups, for example by etherification oresterification; and free carboxyl groups or sulpho groups, for exampleby esterification, inclusive of silylation; and can, if desired, bereleased individually or jointly in a manner known per se after thereaction. For example, amino, hydroxy, mercapto, carboxyl or sulphogroups present in a starting material may be protected, for example inthe form of acylamino groups, such as those mentioned above, for examplethe 2,2,2-trichloroethoxycarbonylamino group, 2-bromoethoxycarbonylaminogroup, 4-methoxybenzyloxycarbonylamino group, ortert.-butyloxycarbonylamino group, or in the form of aryl- or aryl-loweralkylthioamino groups, for example the 2-nitrophenylthioamino group orarylsulphonylamino group, for example the 4-methylphenylsulphonylaminogroup, in the form of 1-lower alkoxycarbonyl-2-propylideneamino groupsor of the o-nitrophenoxyacetylamino group, or of acyloxy groups, such asthose mentioned above, for example the tert.-butyloxycarbonyloxy group,2,2,2-trichloroethoxycarbonyloxy group, 2-bromoethoxycarbonyloxy groupor p-nitrobenzyloxycarbonyloxy group, or corresponding acylmercaptogroups, or in the form of esterified carboxy groups, such as thosementioned above, for example the diphenylmethoxycarbonyl group,p-nitrobenzyloxycarbonyl group, acetonyloxycarbonyl group or2-cyanoethoxycarbonyl group, or of substituted sulpho groups, such asthe above-mentioned lower alkylsulpho groups, for example themethylsulpho group, and when the reaction is complete may be released,optionally after converting the protective group. For example, a2,2,2-trichloroethoxycarbonylamino group or 2-iodoethoxycarbonylaminogroup or alternatively a p-nitrobenzyloxycarbonylamino group may besplit by treating with suitable reducing agents, such as zinc in thepresence of aqueous acetic acid or hydrogen in the presence of apalladium catalyst; a diphenylmethoxycarbonylamino group ortert.-butylcarbonylamino group may be split by treating with formic acidor trifluoroacetic acid; an aryl- or aryl-lower alkylthioamino group maybe split by treating with a nucleophilic reagent such as sulphurousacid; an arylsulphonylamino group may be split by means of electrolyticreduction; a 1-lower alkoxycarbonyl-2-propylideneamino group by treatingwith aqueous mineral acid, and a tert.-butyloxycarbonyloxy group bytreating with formic or trifluoroacetic acid or a2,2,2-trichloroethoxycarbonyloxy group or p-nitrobenzyloxycarbonyloxygroup may be split by treating with a chemical reducing agent, such aszinc in the presence of aqueous acetic acid, or with hydrogen in thepresence of a palladium catalyst; and a diphenylmethoxycarbonyl groupmay be split by treating with formic or trifluoroacetic acid or byhydrogenolysis; an acetonyloxy- or cyanoethoxycarbonyl group may besplit by treating with bases, such as sodium bicarbonate or1,5-diazabicyclo[5,4,0]undec-5-ene, and a substituted sulpho group bytreating with an alkali metal halide; the splitting may, if desired, ineach case be carried out in stages.

Furthermore, in compounds of the formula I that contain in the groups R₁and R₂ functional substituents such as free amino, hydroxy, carboxy orsulpho groups, these groups may be functionally modified by processesknown per se, for example by acylation or esterification orsubstitution. For example, an amino group may be converted into asulphoamino group by treating with sulphur trioxide, preferably in theform of a complex with an organic base such as a tri-lower alkylamine,for example triethylamine. Also, the reaction mixture obtained byreacting an acid addition salt of 4-guanylsemicarbazide with sodiumnitrite can be reacted with a compound of the formula I in which R₁contains an amino group, and the amino group thus converted into a3-guanylureido group. Furthermore, compounds with aliphatically-bondedhalogen, for example with an optionally substituted α-bromoacetylgrouping, can be reacted with esters of phosphorous acid, such astri-lower alkyl phosphite compounds, and thus be made into correspondingphosphono compounds.

In addition, in resulting compounds functional substituents in theradicals R₁ and R₂ ^(A) may be converted into other functional groups; anitro or azido group, for example, may be converted into an amino groupby treating with hydrogen that is catalytically activated by, forexample, a palladium or platinum oxide catalyst.

The 2-penem compounds of the formula I obtained may be converted in amanner known per se by oxidation with suitable oxidising agents such ashydrogen peroxide, or peracids, for example peracetic acid or3-chloroperbenzoic acid, into their 1-oxides. The 1-oxides of 2-penemcompounds of the formula I obtained may be reduced to the corresponding2-penem compounds of the formula I in a manner known per se by reducingwith suitable reducing agents such as phosphorus trichloride. In thesereactions care must be taken that if necessary free functional groupsare protected and, if desired, subsequently released again.

Salts of compounds of the formula I may be produced in a manner knownper se. For example, salts of such compounds with acid groups can beformed, for example, by treating with metal compounds such as alkalimetal salts of suitable carboxylic acids, for example the sodium salt ofα-ethylcaproic acid, or with ammonia or a suitable organic amine,wherein preferably stoichiometric amounts or only a small excess of thesalt-forming medium is used. Acid addition salts of compounds of theformula I with basic groupings are obtained in the usual manner, forexample by treating with an acid or a suitable anion exchange reagent.Inner salts of compounds of the formula I which contain, for example, asalt-forming amino group and a free carboxyl group may be formed, forexample, by neutralising salts such as acid addition salts to theisoelectric point, for example with weak bases, or by treating withliquid ion exchangers. Salts of 1-oxides of compounds of the formula Iwith salt-forming groups may be produced in an analogous manner.

Salts may be converted in the usual manner into the free compounds;metal and ammonium salts, for example, by treating with suitable acids,and acid addition salts, for example, by treating with a suitable basicagent.

Mixtures of isomers obtained may be separated into the individualisomers by methods known per se: mixtures of diastereomeric isomers, forexample, by fractional crystallisation, adsorption chromatography(column or thin-layer chromatography) or other suitable separatingprocesses. Racemic compounds obtained can be separated into theantipodes in the usual manner, optionally after introducing suitablesalt-forming groupings, for example by forming a mixture ofdiastereoisomeric salts with optically active salt-forming agents,separating the mixture into the diastereoisomeric salts and then intothe free compounds, or by fractional crystallisation from opticallyactive solvents.

In all subsequent conversions of the compounds obtained, the reactionsthat are preferred are those carried out under neutral, alkaline orweakly basic conditions.

The process also includes those embodiments according to which compoundsproduced as intermediate products are used as starting substances andthe remaining process steps are carried out with these, or according towhich the process is interrupted at any stage; furthermore, startingsubstances may be used in the form of derivatives or may be formed insitu, optionally under the conditions of the reaction. For example, astarting material of the formula II in which Z is oxygen may be producedin situ from a compound of the formula II in which Z' is an optionallysubstituted methylidene group, by ozonisation and subsequent reductionof the ozonide formed, analogously to the method given in stage 2,5,whereupon, especially when R₁ is hydrogen, the cyclisation to thecompound of the formula I takes place in the reaction solution.

The starting materials of the formula II, and IIA or IIB used inaccordance with the invention may be produced, for example, according tothe following reaction scheme: ##STR8##

In the compounds of the formulae IV, V,VI and II in the reaction schemeI and in the compounds of the formulae Xa, XI, XII and IVa in thereaction scheme 2, Z' is oxygen, sulphur or alternatively, especiallywhen R₁ is hydrogen, a methylidene group optionally substituted by oneor two substituents Y, which group can be converted by oxidation into anoxo group Z. A substituent Y of this methylidene group is an organicradical, for example one of the organic radicals mentioned under R₁,such as one of the mentioned, optionally substituted, lower-alkyl,cycloalkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower alkylradicals, and especially one of the functionally modified, such asesterified, carboxyl groups. Esterification with an optically activealcohol such as 1-menthol is included. This methylidene group preferablycarries one of the substituents mentioned. The2-methoxycarbonylmethylidene and the 2-(1)-menthyloxycarbonylmethylidenegroup Z' are singled out. The latter can be used for the production ofoptically active compounds of the formulae IV to VI and II.

Stage 1.1

A thioazetidinone of the formula IV is obtained by treating anacyloxyazetidinone of the formula III with a mercapto compound R₁--C(═Z')--SH or with a salt, for example an alkali metal salt such as asodium salt thereof, and, if desired, separating an isomeric mixtureobtained into the individual isomers, if desired converting a group R₁in a compound obtained into a different group R₁, and/or, if desired,converting an optionally substituted methylidene group Z' into an oxogroup Z.

Acyloxyazetidinones of the formula III are known (GermanOffenlegungsschrift No. 1 906 401) or can be produced according to knownmethods. The acyl radical may have the same meaning as the acyl radicalR₁ --CO--. The acyl radical may alternatively be derived from anoptically active acid. A preferred acyl radical is acetyl.

This nucleophilic substitution may be carried out under neutral orweakly basic conditions in the presence of water and optionally awater-miscible organic solvent. The basic conditions may be established,for example, by the addition of an inorganic base such as an alkalimetal or an alkaline earth metal hydroxide, -carbonate or -bicarbonate,for example sodium, potassium or calcium-hydroxide, -carbonate or-bicarbonate. The organic solvents that may be used are, for example,water-miscible alcohols, for example, lower alkanols such as methanol orethanol; ketones, for example lower alkanones such as acetone; amides,for example lower alkanecarboxylic acid amides such asdimethylformamide, and the like. The reaction is usually carried out atroom temperature but can be carried out at elevated or reducedtemperature.

Both an optically inactive (4R,S)-compound of the formula III and acorresponding optically active (4R)- or (4S)-compound can be used in thereaction. A racemic compound of the formula IV obtained can be separatedinto the optically active compounds. The racemic compound of the formulaIV in which R₁ is methyl and Z' represents oxygen is known (K. Clauss etal., Liebigs Ann. Chem. 1974, 539-560).

A mercapto compound R₁ --C(═Z')--SH, in which Z' represents amethylidene group optionally substituted by one or two substituents Y,or a salt thereof, may optionally be produced in situ by treating acorresponding isothiouronium salt of the formula R₁ --C(═Z')--S--C (NH₂)(═NH₂.sup.|).A.sup.⊖, in which A.sup.⊖ represents an anion, for examplethe chloride anion, in water, an alcohol such as methanol or ethanol, ora mixture of water and alcohol, with a base, for example an alkali metalhydroxide such as sodium hydroxide.

Stage 1.2

An α-hydroxy-carboxylic compound of the formula V is obtained byreacting a compound of the formula IV with a glyoxylic acid compound ofthe formula OHC--C(═O)--R₂ ^(A) or a suitable derivative such as ahydrate, hemihydrate or semiacetal, for example a semiacetal with alower alkanol, for example, methanol or ethanol, if desired separating aso-obtained isomeric mixture into the individual isomers, if desiredconverting a group R₁ in a compound obtained into a different group R₁and/or, if desired, converting an optionally substituted methylidenegroup Z' into an oxo group Z.

The compound V is usually obtained as a mixture of the two isomers (withreference to the grouping >CH OH). It is possible, however, also toisolate the pure isomers therefrom.

The addition reaction of the glyoxylic acid ester compound to thenitrogen atom of the lactam ring takes place at room temperature or, ifnecessary, while heating, for example up to approximately 100° C., andin the absence of an actual condensation agent and/or without theformation of a salt. When using the hydrate of the glyoxylic acidcompound, water is formed which, if necessary, is removed bydistillation, for example azeotropically, or by using a suitabledehydration agent such as a molecular sieve. Preferably the process iscarried out in the presence of a suitable solvent, such as, for example,dioxan, toluene or dimethylformamide, or of a solvent mixture, ifdesired or necessary in an inert gas atmosphere, such as a nitrogenatmosphere.

Both an optically inactive (4R,S)-compound of the formula IV and acorresponding optically active (4R)- or (4S)-compound can be used in thereaction. A racemic compound of the formula V obtained can be separatedinto the optically active compounds.

Stage 1.3

Compounds of the formula VI, in which X_(o) represents a reactiveesterified hydroxy group, especially halogen or organic sulphonyloxy,are produced by converting the secondary hydroxy group in a compound ofthe formula V into a reactive esterified hydroxy group, especially intohalogen, for example chlorine or bromine, or into an organicsulphonyloxy group such as lower alkylsulphonyloxy, for examplemethylsulphonyloxy, or arylsulphonyloxy, for example4-methylphenylsulphonyloxy, if desired separating an isomeric mixtureobtained into the individual isomers, if desired converting a group R₁in a compound obtained into a different group R₁ and/or, if desired,converting an optionally substituted methylidene group Z' into an oxogroup Z.

The compound VI may be obtained in the form of mixtures of the isomers(with reference to the grouping >CH X_(o)) or in the form of pureisomers.

The above reaction is carried out by treating with a suitableesterifying agent, using, for example, a halogenating agent such as athionyl halide, for example the chloride, a phosphorus oxyhalide,especially the chloride, or a halophosphonium halide such astriphenylphosphine dibromide or diiodide, and a suitable organicsulphonic acid halide such as the chloride, preferably in the presenceof a basic, primarily an organic basic, agent such as an aliphatictertiary amine, for example triethylamine, diisopropylethylamine or"polystyrene-Hunig base", or a heterocyclic base of the pyridine type,for example pyridine or collidine. Preferably the reaction is carriedout in the presence of a suitable solvent, for example dioxan ortetrahydrofuran, or of a suitable solvent mixture, if necessary whilecooling and/or in an inert gas atmosphere, such as a nitrogenatmosphere.

In a compound of the formula IV obtainable in this manner, a reactiveesterified hydroxy group X_(o) can be converted into a differentreactive esterified hydroxy group in a manner known per se. For example,a chlorine atom can be exchanged for a bromine or iodine atom bytreating the corresponding chlorine compound with a suitable bromine oriodine reagent, especially with an inorganic bromide or iodide salt suchas lithium bromide, preferably in the presence of a suitable solventsuch as ether.

Both an optically inactive (4R,S)-compound of the formula V and acorresponding optically active (4R)- or (4S)-compound can be used in thereaction. A racemic compound of the formula VI obtained can be separatedinto the optically active compounds.

Stage 1.4

A starting material of the formula II is obtained by treating a compoundof the formula VI in which X_(o) represents a reactive esterifiedhydroxy group, with a suitable phosphine compound such as tri-loweralkylphosphine, for example tri-n-butylphosphine, or a triarylphosphine,for example triphenylphosphine or with a suitable phosphite compoundsuch as a tri-lower alkyl phosphite, for example triethyl phosphite, oran alkali metal dimethyl phosphite, or by treating a compound of theformula V with carbon tetrachloride and a phosphine, wherein dependingon the choice of reagent a compound of the formula IIA or IIB can beobtained, if desired converting a group R₁ in a compound obtained into adifferent group R₁, and/or if desired converting an optionallysubstituted methylidene group Z' into an oxo group Z.

The reaction using the compound of the formula VI as starting materialis preferably carried out in the presence of a suitable inert solventsuch as a hydrocarbon, for example hexane, cyclohexane, benzene, tolueneor xylene; or an ether, for example dioxan, tetrahydrofuran ordiethylene glycol dimethyl ether, or of a solvent mixture. Depending onthe reactivity, the operation is carried out while cooling or atelevated temperature, approximately between -10° and +200°, preferablyat approximately 20° to 180°, and/or in an inert gas atmosphere, such asa nitrogen atmosphere. In order to prevent oxidative processes,catalytic amounts of an antioxidant, for example p-hydroquinone, may beadded.

When using a phosphine compound the reaction is usually carried out inthe presence of a basic agent, such as an organic base, for example anamine, such as triethylamine, diisopropylethylamine or"polystyrene-Hunig base", and thus the phosphoranylidene startingmaterial of the formula IIA, which is formed from the correspondingphosphonium salt, is obtained directly.

The reaction using a compound of the formula V as starting material iscarried out in a solvent under mild conditions, that is to say, attemperatures of -10° to approximately 40°, preferably at roomtemperature. An excess of carbon tetrachloride especially to whichmethylene chloride may additionally be added, is used as solvent. Theabove-mentioned tri-lower alkyl- or triarylphosphines, especiallytriphenylphosphine, of which two equivalents are used, are suitablephosphines.

Both an optically inactive (4R,S)-compound of the formula VI or V and acorresponding optically active (4R)- or (4S)-compound may be used in thereaction. A racemic compound of the formula II obtained can be separatedinto the optically active compounds.

The above-mentioned racemic compounds are split into their opticalantipodes by methods known per se.

One of these methods consists in reacting a racemic compound with anoptically active auxiliary substance, separating the resulting mixtureof two diastereoisomeric compounds by means of suitablephysical/chemical methods and then splitting the individualdiastereoisomeric compounds into the optically active startingmaterials.

Particularly suitable racemic compounds for separating into antipodesare those that possess an acidic group, for example the racemic compoundof the compound of the formula I. Others of the described racemiccompounds can be converted into acidic racemic compounds by simplereactions. For example, racemic compounds carrying aldehyde or ketogroups react with a hydrazine derivative carrying acid groups, forexample 4-(4-carboxyphenyl)-semicarbazide to form the correspondinghydrazone derivatives, or compounds containing alcohol groups react witha dicarboxylic acid anhydride, for example phthalic acid anhydride, toform the racemic compound of an acid semiester.

These acidic racemic compounds may be reacted with optically activebases, for example esters of optically active amino acids, or(-)-brucine, (+)-quinidine, (-)-quinine, (+)-cinchonine,(+)-dehydroabietylamine, (+)- and (-)-ephedrine, (+)- and(-)-1-phenylethylamine or their N-mono- or dialkylated derivatives toform mixtures consisting of two diastereoisomeric salts.

In racemic compounds containing carboxyl groups, for example in racemiccompounds that contain a functionally modified carboxymethylidene groupZ', this carboxyl group may already be esterified by, or esterificationmay be carried out by, an optically active alcohol such as (-)-menthol,(+)-borneol, (+)- or (-)-2-octanol, whereupon after subsequent isolationof the desired diastereoisomer, the carboxyl group is released, or thepart of the molecule containing the esterified carboxyl group, forexample the esterified carboxymethylidene radical, is split off.

Racemic compounds containing hydroxy groups may likewise be split intotheir optical antipodes, for which, especially, optically active acidsor their reactive functional derivates that form diastereoisomericesters with the said alcohols are used. Such acids are, for example,(-)-abietic acid, D(+)- and L(-)-malic acid, N-acylated optically activeamino acids, (+)- and (-)-camphanic acid, (+)- and (-)-ketopinic acid,L(+)-ascorbic acid, (+)-camphoric acid, (+)-camphor-10-sulphonicacid(β), (+)- or (-)-α-bromocamphor-π-sulphonic acid, D(-)-quinic acid,D(-)-isoascorbic acid, D(-)- and L(+)-mandelic acid, (+)-1-menthoxyacetic acid, D(-)- and L(+)-tartaric acid and their di-O-benzoyl- anddi-O-p-toluyl derivatives. The acyl radicals of the optically activeacids mentioned may be present, for example, as acyl in compounds of theformula III or as (R₁ --C(═O))-- in compounds of the formulae II and IVto VI, and render possible the splitting of the racemates of suchcompounds. If desired or necessary, when the splitting of the racemiccompound is complete the optically active group R₁ --C(═O)-- can beconverted into a desired optically inactive group R₁ --C(═O)--.

Racemic compounds containing hydroxy groups may be converted into amixture of diastereoisomeric urethanes, for example by reacting withoptically active isocyanates, such as with (+)- or (-)-1-phenylethylisocyanate.

Basic racemic compounds can form diastereoisomeric salts with theabove-mentioned acids. Racemic compounds containing double bonds may beconverted, for example by platinum chloride and(+)-1-phenyl-2-aminopropane, into mixtures of diastereoisomeric complexsalts.

Physical/chemical methods, chiefly fractional crystallisation, aresuitable for separating the diastereoisomeric mixtures. It is alsopossible, however, to use chromatographic methods, above allsolid-liquid chromatography. Readily volatile diastereoisomeric mixturesmay also be separated by distillation or gas chromatography.

Splitting the separated diastereoisomers into the optically activestarting materials is likewise carried out according to customarymethods. The acids or the bases are freed from the salts, for example bytreating with stronger acids or bases respectively than those originallyused. The desired optically active compounds are obtained from theesters and urethanes, for example by alkaline hydrolysis or by reductionwith a complex hydride such as lithium aluminium hydride.

A further method of separating the racemic compounds consists in thechromatography on optically active absorption layers, for example onunrefined sugar.

According to a third method, the racemic compounds are dissolved inoptically active solvents and the more sparingly soluble opticalantipode is crystallised out.

In a fourth method the different reactivity of the optical antipodes incomparison with the biological material, such as microorganisms orisolated enzymes, is used.

According to a fifth method, the racemic compounds are dissolved and oneof the optical antipodes is crystallised out by injecting a small amountof an optically active product obtained according to the above methods.

Optically active trans-compounds of the formula IVa that can be usedaccording to the invention may also be produced in accordance with thefollowing reaction scheme: ##STR9##

In the compounds of the formulae VII to XII, R₂ ^(A) preferablyrepresents lower alkoxy, especially methoxy.

Stage 2.1

An oxide of a penicillanic acid compound of the formula VIII is obtainedby oxidising a penicillanic acid compound of the formula VII in the1-position. The oxidation is carried out in a manner known per se withsuitable oxidising agents, such as hydrogen peroxide or inorganic ororganic peracids. Suitable inorganic peracids are, for example, periodicor persulphuric acid. Suitable organic peracids are, for example,percarboxylic acids, such as performic acid, peracetic acid,trifluoroperacetic acid, permaleic acid, perbenzoic acid,3-chloroperbenzoic acid or monoperphthalic acid, or persulphonic acids,for example p-toluenepersulphonic acid. The peracids may also beproduced in situ from hydrogen peroxide and the corresponding acids. Theoxidation is carried out under mild conditions, for example attemperatures of approximately -50° to approximately +100°, preferably atapproximately -10° to approximately +40°, in an inert solvent.

Starting compounds of the formula VII are known or can be producedaccording to known processes. For example, they may be obtained byhydrogenation of potassium-6α-bromopenicillanic acid and subsequentesterification of the carboxyl group [E. Evrard, M. Claesen and H.Vanderhaege, Nature 201, 1124 (1964)] or by hydrogenation of6,6-dibromopenicillanic acid esters, for example the methyl ester [J. P.Clayton, J. Chem. Soc. (C), 2123 (1969)].

Stage 2.2

A 3-methylenebutyric acid compound of the formula IX is obtained bytreating a 1-oxide of a penicillanic acid compound of the formula VIIIwith a mercapto compound R°--SH.

In the mercapto compound R°--SH and in the reaction product of theformula IX, R° is an optionally substituted aromatic heterocyclicradical having up to 15, preferably up to 9, carbon atoms, and at leastone ring nitrogen atom, and optionally a further ring hetero atom, suchas oxygen or sulphur, which radical is bonded to the thio group --S-- byone of its ring carbon atoms that is bonded to a ring nitrogen atom by adouble bond. Radicals of this type are monocyclic or bicyclic and may besubstituted, for example by lower alkyl, such as methyl or ethyl, loweralkoxy, such as methoxy or ethoxy, halogen, such as fluorine orchlorine, or aryl, such as phenyl.

Radicals R° of this type are, for example, monocyclic five-memberedthiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclicradicals of aromatic character, especially monocyclic five-membereddiazacyclic, oxazacyclic and thiazacyclic radicals of aromaticcharacter, and/or primarily the corresponding benzdiazacyclic,benzoxazacyclic or benzthiazacyclic radicals, in which the heterocyclicpart is five-membered and has an aromatic character, wherein in R°radicals a substitutable ring nitrogen atom may be substituted, forexample by lower alkyl. Representative of such R° groups are1-methylimidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl,1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methylbenzimidazol-2-yl,benzoxazol-2-yl and especially benzthiazol-2-yl.

The reaction is carried out in an inert solvent, such as an aliphatic oraromatic hydrocarbon, for example benzene or toluene, while warming upto the reflux temperature of the solvent used.

Stage 2.3

A 3-methylcrotonic acid compound of the formula X is obtained byisomerising a 3-methylenebutyric acid compound of the formula IX bytreating with a suitable basic agent.

Suitable basic agents are, for example, organic nitrogen bases such astertiary amines, for example tri-lower alkylamines such as triethylamineor Hunig base, or inorganic bases, which are used in an inert solvent,such as an optionally halogenated hydrocarbon, for example methylenechloride, at room temperature or optionally slightly reduced or elevatedtemperature.

Stage 2.4

A thio compound of the formula XI is obtained by treating a compound ofthe formula X with a suitable reducing agent and simultaneously orsubsequently reacting with an acylation derivative of a carboxylic acidof the formula R₁ --C(═Z)--OH, or, when Z' represents a methylidenegroup optionally substituted by Y, reacting with an alkyne of theformula R₁ --C.tbd.C--Y, and, if desired, converting a group R₁ in acompound so obtained into a different group R₁, and/or, if desired,converting an optionally substituted methylidene group Z' into an oxogroup Z.

Suitable reducing agents are, for example, hydride reducing agents suchas alkali metal borohydrides, for example sodium borohydride, or alsozinc in the presence of a carboxylic acid, for example a carboxylic acidof the formula R₁ --C(═Z)--OH. The hydride reducing agents are usuallyused in the presence of suitable solvents, such as dimethylformamide.The hydride reduction is preferably carried out in dimethylformamidewith sodium borohydride at temperatures of approximately -50° toapproximately -10°, preferably at approximately -20°, whereupon at thesame temperature the acylating agent and optionally a tertiary base,such as pyridine, are added. The reduction with zinc and a carboxylicacid is optionally carried out in a solvent, for which the carboxylicacid, if liquid, can itself be used, at temperatures of approximately-10° to approximately +50°, preferably at approximately 0° to roomtemperature. The acylating agent can be added to the reduction mixturefrom the beginning or when reduction is complete and optionally afterevaporating off the carboxylic acid used and/or the solvent. Suitableacylating agents are especially anhydrides of the carboxylic acidsmentioned, such as symmetric anhydrides, for example acetic anhydride,or mixed anhydrides, preferably those with halogen hydracids, that isthe corresponding carboxylic acid halides, for example the chlorides andbromides, such as acetyl>bromide. For example, a compound of the formulaX may be converted with zinc in a mixture of acetic acid and aceticanhydride at 0° to approximately 20° into a compound of the formula XI,in which R₁ is methyl. Owing to the reduced risk of racemisation, thezinc/carboxylic acid reduction is preferred. The alkyne can also beadded to the reduction solution from the beginning or when reduction iscomplete. The addition of the 4-mercaptoazetidin-2-one, produced as anintermediate product in the reduction, to the triple bond of the alkynetakes place spontaneously at the reduction temperature.

Stage 2.3a

A thio compound of the formula XI is also obtained by isomerising acompound of the formula Xa in accordance with the reaction conditions ofstage 2.3 by treating with a suitable basic agent, if desired convertinga group R₁ in a compound obtained into a different group R₁, and/or, ifdesired, converting an optionally substituted methylidene group Z' intoan oxo group Z.

Stage 2.4a

A compound of the formula Xa is obtained by treating a3-methylenebutyric acid compound of the formula IX in accordance withthe reaction conditions of stage 2.4 with a suitable reducing agent, andsimultaneously or subsequently reacting with an acylating derivative ofa carboxylic acid of the formula R₁ --C(═Z)--OH, or, when Z' representsa methylidene group optionally substituted by Y, with an alkyne of theformula R₁ --C.tbd.C--Y, and, if desired, converting a group R₁ in acompound obtained into a different group R₁, and/or, if desired,converting an optionally substituted methylidene group Z' into an oxogroup Z.

Stage 2.5

A 2-oxoacetic acid compound of the formula XII is obtained by ozonisinga compound of the formula XI and splitting the ozonide formed to the oxogroup by means of reduction, and if desired converting a group R₁ in acompound obtained into a different group R₁, and/or, if desired,converting an optionally substituted methylidene group Z' into an oxogroup Z.

The ozonisation is usually carried out with an ozone/oxygen mixture inan inert solvent, such as a lower alkanol, for example methanol orethanol, a lower alkanone, for example acetone, an optionallyhalogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, forexample a halogen-lower alkane, such as methylene chloride or carbontetrachloride, or in a solvent mixture, including an aqueous mixture,preferably while cooling, for example at temperatures of approximately-90° to approximately 0°.

An ozonide obtained as intermediate product is, usually without havingto be isolated, split reductively to form a compound of the formula XII,wherein catalytically activated hydrogen, for example hydrogen in thepresence of a heavy metal hydrogenating catalyst, such as a nickelcatalyst or palladium catalyst, preferably on a suitable carriermaterial, such as calcium carbonate or carbon, is used; or chemicalreducing agents, such as reducing heavy metals, including heavy metalalloys or amalgams, for example zinc, in the presence of a hydrogendonor such as an acid, for example acetic acid, or of an alcohol, forexample a lower alkanol, are used; or reducing inorganic salts, such asalkali metal iodides, for example sodium iodide, or alkali metalbisulphites, for example, sodium bisulphite, in the presence of ahydrogen donor, such as an acid, for example acetic acid, or water, areused; or reducing organic compounds such as formic acid are used. It isalso possible to use as reducing agents compounds that may readily beconverted into corresponding epoxy compounds or oxides, wherein theepoxide formation can take place on account of a C,C-double bond and theoxide formation on account of an oxide-forming hetero atom, such as asulphur, phosphorus or nitrogen atom. Compounds of this type are, forexample, suitably substituted ethylene compounds (which are convertedinto ethylene oxide compounds in the reaction), such astetracyanoethylene, in particular suitable sulphide compounds (which inthe reaction are converted into sulphoxide compounds), such as di-loweralkyl sulphides, especially dimethyl sulphide, suitable organicphosphorus compounds, such as a phosphine, which may contain optionallysubstituted aliphatic or aromatic hydrocarbon radicals as substituents(and which in the reaction is converted into a phosphine oxide), such astri-lower alkylphosphines, for example tri-n-butylphosphine, ortriarylphosphines, for example triphenylphosphine, or phosphites, whichcontain optionally substituted aliphatic hydrocarbon radicals assubstituents (and in the reaction are converted into phosphoric acidtriesters), such as tri-lower alkyl phosphites, usually in the form ofcorresponding alcohol adduct compounds, such as trimethyl phosphite, orphosphorous acid triamides, which contain optionally substitutedaliphatic hydrocarbon radicals as substituents such as hexa-lower alkylphosphorous acid triamides, for example hexamethyl phosphorous acidtriamide, the latter preferably in the form of a methanol adduct, orsuitable nitrogen bases (which in the reaction are converted into thecorresponding N-oxides), such as heterocyclic nitrogen bases of aromaticcharacter, for example bases of the pyridine type and especiallypyridine itself. The splitting of the usually unisolated ozonide isnormally carried out under the conditions used for its manufacture, thatis to say, in the presence of a suitable solvent or solvent mixture, andwhile cooling or heating gently, wherein preferably temperatures ofapproximately -10° C. to approximately +25° C. are used and the reactionusually terminates at room temperature.

Stage 2.6

A compound of the formula IVa is obtained by solvolysing a compound ofthe formula XII and, if desired, converting a group R₁ in a compound soobtained into a different group R₁, and/or, if desired, converting anoptionally substituted methylidene group Z' into an oxo group Z.

The solvolysis may be carried out by hydrolysis or preferablyalcoholysis, wherein the reaction is usually carried out with a loweralkanol, for example methanol or ethanol. The alcoholysis is preferablycarried out in the presence of water and an organic solvent, such as alower alkanecarboxylic acid-lower alkyl ester, for example ethylacetate, preferably at room temperature, if necessary while cooling orheating. The α-ketocarboxylic acid of the formula XIII does notnecessarily have to be isolated. If, for example, the ozonide is splitin the presence of a solvolysing agent, such as, for example, water, acompound of the formula IVa can be obtained directly.

In the compounds IV to XII, II and IVa, a group R₁ or R₂ ^(A) can beconverted according to methods known per se into a different R₁ or R₂^(A) group respectively, wherein it is possible to use the same methodsas are given for converting these substituents in the compounds of theformula I.

In the compounds IV to VI and II, an optionally substituted methylidenegroup Z' may be converted into an oxo group Z by ozonisation andsubsequent reduction of the ozonide formed, according to the processdescribed in stage 2.5

The invention likewise includes the new intermediate products, such asthose of the formulae IV to XIII and especially of the formula II, andthe processes for their production.

The pharmacologically usable compounds of the invention may be used, forexample, for the production of pharmaceutical preparations that containan effective amount of the active substance together or in admixturewith inorganic or organic, solid or liquid, pharmaceutically usuablecarrier substances that are suitable for enteral or parenteraladministration. For example, tablets or gelatin capsules that containthe active substance together with diluents, for example lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, andlubricants, for example silica, talcum, stearic acid or salts thereof,such as magnesium or calcium stearate, and/or polyethyleneglycol;tablets also contain binders, for example magnesium aluminium silicate,starches such as maize, wheat, rice or arrowroot starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrating agents, forexample starches, agar, alginic acid or a salt thereof, such as sodiumalginate, and/or effervescing mixtures, or adsorbents, dyestuffs,flavouring substances and sweeteners. Also, the new pharmacologicallyactive compounds can be used in the form of injectable, for exampleintravenously administrable, preparations or in the form of infusionsolutions. Solutions of this type are preferably isotonic aqueoussolutions or suspensions, wherein these can be produced before use forexample from lyophilised preparations that contain the active substancealone or together with a carrier material, for example mannitol. Thepharmaceutical preparations may be sterilised and/or contain auxiliarysubstances, for example preservatives, stabilisers, wetting agentsand/or emulsifiers, solubilisers, salts for regulating the osmoticpressure and/or buffers. The pharmaceutical preparations of theinvention which, if desired, may contain other pharmacologicallyvaluable substances are produced in a manner known per se, for exampleby means of conventional mixing, granulating, pill-coating, dissolvingor lyophilising processes and contain from approximately 0.1% to 100%,especially from approximately 1% to approximately 50%, in the case ofthe lyophilisate up to 100%, of the active substance.

Referring to the present description, organic radicals referred to as"lower", unless expressly defined, contain up to 7, preferably up to 4,carbon atoms; acyl radicals contain up to 20, preferably up to 12, andprimarily up to 7, carbon atoms.

The following Examples serve to illustrate the invention; temperaturesare in degrees Centigrade. The following abbreviations are used:TLC=thin layer chromatogram over silica gel; sh=shoulder.

EXAMPLE 1 (4R,S)-4-Acetylthio-2-oxoazetidine

A solution of 0.12 ml of thioacetic acid in 1.6 ml of 1N sodiumhydroxide solution is added dropwise, at room temperature, to a solutionof 138 mg (1.07 mmol) of (4R,S)-4-acetoxyazetidin-2-one in 0.4 ml ofwater and 0.1 ml of acetone, and the mixture is stirred at the sametemperature overnight. The reaction mixture is exhaustively extractedwith methylene chloride. The combined organic phases are dried oversodium sulphate and concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (4:1 to 3:2)and yields the title compound with the following physicochemicalproperties:

TLC: R_(f) =0.29 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.6, 5.9 and 8.85μ.

EXAMPLE 2 2-[(4R,S)-4-Acetylthio-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

A solution of 12.9 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzylester in a mixture of 240 ml of toluene and 60 ml of dimethylformamideis added at room temperature to 3.3 g (22.75 mmol) of(4R,S)-4-acetylthio-2-oxoazetidine. After adding freshly dried molecularsieves, the mixture is stirred under nitrogen overnight at roomtemperature and subsequently for 2 hours at 50°. The molecular sievesare filtered off, washed with toluene and the filtrate and washingliquid are concentrated together in vacuo. The residue is dried underhigh vacuum and chromatographed over silica gel with toluene/ethylacetate (9:1). After elution of the unreacted 2-ethoxy-2-hydroxyaceticacid p-nitrobenzyl ester, the title compound having the followingphysico-chemical properties is eluted:

TLC: R_(f) =0.31 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.8, 5.6, 5.7, 5.87, 6.55 and 7.4μ.

EXAMPLE 32-[(4R,S)-4-Acetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 2 g of2-[(4R,S)-4-acetylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester in 40 ml of absolute dioxan is added to a solutionof 5.5 g of poly-Hunig base in 20 ml of absolute dioxan that has alreadybeen stirred for 30 minutes. After adding a solution of 1.87 ml (3.5equivalents) of thionyl chloride in 30 ml of absolute dioxan, thereaction mixture is stirred for 5 hours at room temperature undernitrogen. The poly-Hunig base is filtered off and the filtrate isconcentrated in vacuo.

(b) The crude 2-[(4R,S)-4-acetylthio-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 107 ml of absolutedioxan, 7 g of poly-Hunig base and 2.85 g of triphenylphosphine areadded and the mixture is stirred under nitrogen for 15 hours at 50°. Thepoly-Hunig base is filtered off, washed with dioxan and the filtrate andwashing liquid are concentrated together in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate and yieldsthe title compound having the following physicochemical properties:

TLC: R_(f) =0.24 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.67, 5.9, 6.15, 6.55, 7.42, 9.05 and 9.25μ.

(c) The same title compound may alternatively be obtained by stirring0.44 mmol of 2-[(4R,S)-4-acetylthio-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester in a mixture of 2 ml of methylene chloride and0.2 ml of carbon tetrachloride with 1 mmol of triphenylphosphine for 4hours at room temperature and for 30 minutes at 40° C., diluting thereaction mixture with methylene chloride, washing with aqueous sodiumbicarbonate solution, drying over sodium sulphate, concentrating invacuo and chromatographing the residue over silica gel withtoluene/ethyl acetate (2:3).

EXAMPLE 4 (5R,S)-2-Methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 100 mg(0.167 mmol) of2-[(4R,S)-4-acetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 50 ml of absolute toluene, and the mixtureis stirred overnight at 90° under nitrogen. The solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (19:1). The title compound is obtained in the formof yellowish crystals having the following physico-chemical properties:

melting point: 130°-132°; TLC: R_(f) =0.54 (toluene/ethyl acetate 2:3);UV spectrum (ethanol): λ_(max) =308 nm (ε=10036), 262 nm (ε=13090); IRspectrum (CH₂ Cl₂): absorption bands at 5.57, 5.82, 6.3, 6.55, 7.4, 7.6and 8.3μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.25=2H, m; 7.65=2H,m; 5.65=1H, q; 5.35=2H, m; 3.4-3.9=2H, m; 2.4=3H, s.

EXAMPLE 5 (5R,S)-2-Methyl-2-penem-3-carboxylic acid

(a) 2 ml of 0.2M aqueous sodium bicarbonate solution and 100 mg of 10%palladium/carbon catalyst are added to a solution of 50 mg of(5R,S)-2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 3 ml ofabsolute ethyl acetate and the mixture is stirred at normal pressure for35 minutes under hydrogen. The hydrogenated mixture is filtered off fromthe catalyst over diatomaceous earth, the residue is washed with 0.7 mlof 0.2M sodium bicarbonate solution and ethyl acetate, and the filtrateand washing liquid are freed of ethyl acetate in vacuo. The remainingaqueous solution is acidified with 5 ml of 5% aqueous citric acidsolution and exhaustively extracted with methylene chloride. Thecombined organic phases are dried over sodium sulphate, filtered,concentrated in vacuo and dried under high vacuum. The title compoundobtained has the following physico-chemical properties:

IR spectrum (CH₂ Cl₂): absorption bands at 5.57 and 5.95μ;

NMR spectrum (DMSO d6/100 Mc, in ppm): 5.65=1H, q; 3.3-3.9=2H, m (+H₂O); 2.28=3H, s.

(b) 28 ml of 0.2M aqueous sodium bicarbonate solution and 1 g of 10%palladium/carbon catalyst are added to a solution of 700 mg (2.18 mmol)of (5R,S)-2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 42ml of absolute ethyl acetate and the mixture is stirred at normalpressure for 90 minutes under hydrogen. The hydrogenated mixture isfiltered off from the catalyst over diatomaceous earth, the residue iswashed with 0.2M sodium bicarbonate solution and ethyl acetate, and thefiltrate and washing liquid are combined. The aqueous phase is separatedoff, washed with methylene chloride, acidified with 5 ml of 5% aqueouscitric acid solution and exhaustively extracted with methylene chloride.The combined organic phases are dried over sodium sulphate, filtered,concentrated in vacuo and dried under high vacuum. The title compoundobtained is crystallised from diethyl ether/acetone and has thefollowing physico-chemical properties:

melting point: 140°-167° (undefined, with decomposition);

TLC: R_(f) =0.17 (toluene/ethyl acetate 3:2+5% acetic acid),

IR spectrum (KBr): absorption bands at 3.4, 3.6, 3.95, 5.62, 6.0, 6.37,7.0, 7.85 and 8.15μ; NMR spectrum as above.

In a similar manner it is possible starting from a correspondingoptically active (5R)- or (5S)-compound, to produce the optically active(5R)- and (5S)-2-methyl-2-penem-3-carboxylic acid respectively, whichcan also be obtained by resolving the racemic compound with an opticallyactive base.

EXAMPLE 6 Sodium salt of (5R,S)-2-methyl-2-penem-3-carboxylic acid

A solution of 50 mg of (5R,S)-2-methyl-2-penem-3-carboxylic acid in theequivalent amount of aqueous sodium bicarbonate solution is concentratedin vacuo and dried under high vacuum.

EXAMPLE 7 (4R,S)-4-Phenylacetylthio-2-oxoazetidine

A solution of 5 g (33 mmol) of phenylthioacetic acid in 33 ml of 1Naqueous sodium hydroxide solution is added dropwise, at roomtemperature, to a solution of 4.24 g (33 mmol) of(4R,S)-4-acetoxyazetidin-2-one in 20 ml of water and the mixture isstirred overnight at the same temperature. The precipitated titlecompound is filtered off, and recrystallised twice from ethylenechloride/hexane.

Melting point: 78°;

IR spectrum (CH₂ Cl₂): absorption bands at 3.0, 5.65, 5.95, 6.73, 7.15,7.5, 7.87, 8.65, 9.21, 10.25, 10.6 and 11.15μ.

EXAMPLE 82-[(4R,S)-4-Phenylacetylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester

2.87 g (11.24 mmol) of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl esteris added at room temperature to a solution of 1.244 g (5.62 mmol) of(4R,S)-4-phenylacetylthio-2-oxoazetidine in 42 ml of toluene and 11 mlof dimethylformamide. After the addition of freshly dried molecularsieves A4, the mixture is stirred at room temperature overnight undernitrogen. The molecular sieves are filtered off and the filtrate isconcentrated in vacuo. The residue is dried under high vacuum andchromatographed over silica gel with toluene/ethyl acetate (9:1 and4:1). After eluting the unreacted 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester, the title compound having the followingphysico-chemical properties is eluted:

TLC: R_(f) =0.38 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.85, 2.95, 5.6, 5.7 (sh), 5.9, 6.55 and 7.4μ. Thisproduct still contains some 2-ethoxy-2-hydroxyacetic acid p-nitrobenzylester but can be used in the following reaction without furtherpurification.

EXAMPLE 92-[(4R,S)-4-Phenylacetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 522 mg (1.21 mmol) of2-[(4R,S)-4-phenylacetylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester in 10 ml of absolute dioxan is added to a solutionof 1.5 g of poly-Hunig base in 5 ml of absolute dioxan that has alreadybeen stirred for 30 minutes. After adding a solution of 0.304 ml (3.5equivalents) of thionyl chloride in 8 ml of absolute dioxan, thereaction mixture is stirred for 3 hours at room temperature undernitrogen. The poly-Hunig base is filtered off and the filtrate isconcentrated in vacuo. The2-[(4R,S)-4-phenylacetylthio-2-oxo-1-azetidinyl]-2-chloroacetic acidp-nitrobenzyl ester is used in the following reaction without furtherpurification.

TLC: R_(f) =0.62 (toluene/ethyl acetate 1:1); IR spectrum (in CH₂ Cl₂):absorption bands at 5.61, 5.70, 6.25, 6.55, 7.45 and 9.0μ.

(b) The crude2-[(4R,S)-4-phenylacetylthio-2-oxo-1-azetidinyl]-2-chloroacetic acidp-nitrobenzyl ester obtained is dissolved in 25 ml of absolute dioxan,481 mg of triphenylphosphine and 2 g of poly-Hunig base are added andthe mixture is stirred overnight at 50° under nitrogen. The poly-Hunigbase is filtered off, washed with dioxan and the filtrate and washingliquid are concentrated together in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1,and 1:1) and yields the title compound with the followingphysico-chemical properties:

TLC: R_(f) =0.27 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.33, 5.70, 5.90, 6.15, 6.57, 6.68, 6.96, 7.29,7.42, 7.90, 8.25, 8.40, 9.05, 9.25, 9.70, 9.85 and 10.0μ.

EXAMPLE 10 (5R,S)-2-Benzyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 268 mg(0.167 mmol) of2-[(4R,S)-4-phenylacetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 75 ml of absolute toluene and the mixture isstirred under nitrogen for 36 hour at 90°. The solvent is evaporated offin vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (19:1). The title compound is obtained in the formof colourless crystals having the following physico-chemical properties:

melting point: 115° (from methylene chloride/diethyl ether).

IR spectrum (CH₂ Cl₂): absorption bands at 3.33, 3.45, 5.6, 5.83, 6.25,6.36, 6.58, 7.45, 7.65, 8.4, 8.85, 9.45, 9.95 and 11.75μ; NMR spectrum(in CDCl₃ /100 Mc, in ppm): 8.18, 2H, d, J=9 Hz; 7.58, 2H, d, J=9 Hz;7.24, 5H, s; 5.57, 1H, qu, J_(cis) =4 Hz, J_(trans) =2 Hz; 5.35, 2H, AB;4.17, 2H, AB; 3.59, 2H, ABX; J_(AX) =2 Hz, J_(BX) =4 Hz.

EXAMPLE 11 (5R,S)-2-Benzyl-2-penem-3-carboxylic acid

3 ml of a 0.2M aqueous solution of sodium bicarbonate solution and 150mg of 10% palladium/carbon catalyst are added to a solution of 78 mg of(5R,S)-2-benzyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 4.5 mlof absolute ethyl acetate and the mixture is stirred at normal pressurefor 30 minutes under hydrogen. The hydrogenated mixture is filtered offfrom the catalyst over diatomaceous earth and the residue is washed with2 ml of 0.2M sodium bicarbonate solution and ethyl acetate. The aqueoussolution is separated from the filtrate, acidified with 0.1M aqueouscitric acid solution and exhaustively extracted with methylene chloride.The combined methylene chlorine extracts are dried over sodium sulphate,filtered, concentrated in vacuo and dried under high vacuum. The titlecompound is obtained in the form of colourless needles and has thefollowing physico-chemical properties:

melting point 113°-132°; IR spectrum (CH₂ Cl₂): absorption bands at 5.6,6.0, 6.42, 7.45, 7.87 and 8.43μ.

EXAMPLE 12 (4R,S)-4-(2-Furoylthio)-2-oxoazetidine

A solution of 6.4 g (50.7 mmol) of furan-2-thiocarboxylic acid in 51 mlof 1N sodium hydroxide solution is added dropwise at room temperatureunder nitrogen to a solution of 5.15 g (35 mmol) of(4R,S)-4-acetoxyazetidin-2-one in 20 ml of water and the mixture isstirred at the same temperature for 4 to 6 hours. The reaction mixtureis exhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(4:1) and yields the title compound having a melting point of 94°-95°.

TLC: R_(f) =0.34 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.97, 5.6, 6.05, 6.37 and 6.85μ.

EXAMPLE 132-[(4R,S)-4-(2-Furoylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester

A solution of 7.6 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl esterin 150 ml of toluene and 38 ml of dimethylformamide is added at roomtemperature to 2.4 g of (4R,S)-4-(2-furoylthio)-2-oxoazetidine. Afteradding freshly dried molecular sieves, the mixture is stirred undernitrogen for 15 hours at room temperature and then for 2 hours at 50°.The molecular sieves are filtered off, washed with toluene and thefiltrate and washing liquid are concentrated together in vacuo. Theresidue is chromatographed over 200 g of silica gel with toluene/ethylacetate (9:1 to 8:2). After elution of the unreacted2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the title compoundwith the following physico-chemical properties is eluted:

TLC: R_(f) =0.33 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.87, 5.52, 5.6, 6.05; 6.55; 6.85 and 7.42μ.

EXAMPLE 142-[(4R,S)-4-(2-Furoylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 4.9 g of2-[(4R,S)-4-(2-furoylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester in 90 ml of absolute dioxan is added to a solutionof 18 g of poly-Hunig base in 45 ml of absolute dioxan that has alreaybeen stirred for 30 minutes. After adding a solution of 3.45 ml ofthionyl chloride in 30 ml of absolute dioxan, the reaction mixture isstirred for one hour at room temperature under nitrogen. The poly-Hunigbase is filtered off and the filtrate is concentrated in vacuo.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.57, 6.02, 6.55, 7.4, 8.9and 11.4μ.

(b) The crude2-[(4R,S)-4-(2-furoylthio)-2-oxo-1-azetidinyl]-2-chloroacetic acidp-nitrobenzyl ester obtained is dissolved in 216 ml of absolute dioxan,stirred together with 18 g of poly-Hunig base for 30 minutes undernitrogen and, after adding 6.15 g of triphenylphosphine, is stirred fora further 15 hours at 50° under nitrogen. The poly-Hunig base isfiltered off, washed with dioxan and the filtrate and washing liquid areconcentrated together in vacuo. The residue is chromatographed over 200g of silica gel with toluene/ethyl acetate (8:2 and 7:3) and yields thetitle compound with the following physico-chemical properties:

TLC: R_(f) =0.35 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂ :absorption bands at 5.67, 6.02, 6.15, 6.57, 7.42, 9.02, 9.25 and 9.85μ.

EXAMPLE 15 (5R,S)-2-Fur-2-yl-2-penem-3-carboxylic acid p-nitrobenzylester

A catalytic amount of hydroquinone is added to a solution of 1 g (1.54mmol) of2-[(4R,S)-4-(2-furoylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 450 ml of absolute toluene and the mixtureis stirred under nitrogen for 48 hours at 90°. The solvent is evaporatedoff in vacuo and the residue is chromatographed over 50 g of silica gelwith toluene/ethyl acetate (19:1). The title compound is obtained in theform of yellowish crystals having the following physico-chemicalproperties:

melting point: 161°-163° (diethyl ether/methylene chloride);

TLC: R_(f) =0.64 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.57, 5.85, 6.55, 7.42, 7.62, 8.2, 8.35 and 8.5μ;NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.22=2H, m; 7.75-7.5=4H, m;6.55=1H, dd; 5.68=1H, dd; 5.37, 2H, m; 3.7=2H, m.

EXAMPLE 16 (5R,S)-2-Fur-2-yl-2-penem-3-carboxylic acid

4 ml of 0.2N aqueous sodium bicarbonate solution and 200 mg of 10%palladium/carbon catalyst are added to a solution of 100 mg of(5R,S)-2-fur-2-yl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 6 mlof absolute ethyl acetate and the mixture is stirred at normal pressurefor 75 minutes under hydrogen. The hydrogenated mixture is filtered offfrom the catalyst over diatomaceous earth, the residue is washed with0.2N sodium bicarbonate solution and ethyl acetate, and the filtrate andwashing liquid are combined and the phases separated. The aqueous phaseis washed with methylene chloride, acidified with 5% aqueous citric acidsolution and extracted with methylene chloride. The methylene chloridephases are dried over sodium sulphate, filtered, concentrated in vacuoand dried under high vacuum. The title compound obtained has thefollowing physico-chemical properties:

TLC: R_(f) =0.34 (toluene/ethyl acetate/acetic acid 60:40:5);

IR spectrum (KBr); absorption bands at 3.35-3.55, 5.6, 5.95, 6.57, 7.07,7.7, 7.82, 8.15, 8.35μ; NMR spectrum (DMSO d6/100 Mc, in ppm): 7.9, 1H,m; 7.6, 1H, m; 6.74, 1H, m; 5.75, 1H, m; 4.0-3.4, 2H, m.

EXAMPLE 17 (4R,S)-4-(3-Dimethylaminobenzoylthio)-2-oxoazetidine

A solution of 864 mg (4.77 mmol) of 3-dimethylaminothiobenzoic acid in4.77 ml of 1N sodium hydroxide solution and 5 ml of tetrahydrofuran isadded dropwise at 0° to a solution of 616 mg (4.77 mmol) of(4R,S)-4-acetoxyazetidin-2-one in 13 ml of water and the mixture isstirred overnight at room temperature. The reaction mixture is extractedwith 50 ml of methylene chloride. The organic phase is washed withwater, dried over sodium sulphate and concentrated in vacuo. The residueis chromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1and 2:1) and yields the title compound which after recrystallising frommethylene chloride/pentane is obtained in the form of green-yellowcrystals melting at 117°.

IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 3.5, 5.63, 6.03, 6.25,6.68, 7.0, 7.40, 8.28, 8.62, 10.22, 10.82 and 11.10μ.

EXAMPLE 182-[(4R,S)-4-(3-Dimethylaminobenzoylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

714 mg (2.8 mmol) of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl esterare added at room temperature to a solution of 305 mg (1.38 mmol) of(4R,S)-(3-dimethylaminobenzoylthio)-2-oxoazetidine in a mixture of 8 mlof toluene and 2 ml of dimethylformamide. After adding freshly driedmolecular sieves A4, the mixture is stirred overnight at roomtemperature under nitrogen. The molecular sieves are filtered off,washed with toluene and the filtrate and washing liquid are concentratedtogether in vacuo. The residue is chromatographed over silica gel withtoluene and toluene/ethyl acetate (9:1 and 4:1). After eluting theunreacted 3-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the titlecompound is eluted; it still contains some 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester but can be used in the subsequent reaction withoutfurther purification:

TLC: R_(f) =0.33 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.86, 3.42, 5.62, 5.69, 6.03, 6.23, 6.54, 7.41,8.25, 9.15, 10.20, 10.83 and 11.22μ. Recrystallisation from methylenechloride/diethyl ether yields the pure title compound in the form ofred-yellow platelets melting at 148°.

EXAMPLE 192-[(4R,S)-4-(3-Dimethylaminobenzoylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester

A solution of 699 mg of2-[(4R,S)-4-(3-dimethylaminobenzoylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester in 10 ml of absolute dioxan is added to asolution of 2 g of poly-Hunig base in 7.5 ml of absolute dioxan that hasalready been stirred for 30 minutes. After slowly adding 0.38 ml (3.5equivalents) of thionyl chloride, the reaction mixture is stirred for1.5 hours at room temperature under nitrogen. The poly-Hunig base isfiltered off and the filtrate is concentrated in vacuo. The titlecompound obtained is used in the subsequent reaction without furtherpurification.

TLC: R_(f) =0.62 (toluene/ethyl acetate 1:1); IR spectrum (in CH₂ Cl₂):absorption bands at 3.4, 5.62, 5.67, 6.0, 6.25, 6.55, 6.68, 7.45, 7.65,8.30, 8.50, 9.10, 10.4, 10.85, 11.75μ.

EXAMPLE 202-[(4R,S)-4-(3-Dimethylaminobenzoylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

2 g of poly-Hunig base and 614 mg of triphenylphosphine are added to asolution of 747 mg of the obtained crude2-[(4R,S)-4-(3-dimethylaminobenzoylthio)-2-oxo-1-azetidinyl]-2-chlororaceticacid p-nitrobenzyl ester in 30 ml of absolute dioxan, and the mixture isstirred overnight at 50° under nitrogen. The poly-Hunig base is filteredoff and the filtrate is concentrated in vacuo. The residue is taken upin methylene chloride, washed with aqueous sodium bicarbonate solution,dried over sodium sulphate and concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 and 4:1) and yields the title compound in the form of a green-yellow oil havingthe following physico-chemical properties:

TLC: R_(f) =0.23 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.45, 5.69, 6.02, 6.23, 6.57, 6.68, 6.97, 7.42,8.28, 9.03, 9.25 and 10.83μ.

EXAMPLE 21 (5R,S)-2-(3-Dimethylaminophenyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 448 mg(0.64 mmol) of2-[(4R,S)-4-(3-dimethylaminobenzoylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneacticacid p-nitrobenzyl ester in 100 ml of absolute toluene and the mixtureis stirred for 90 hours at 90° under nitrogen. The solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (19:1). The title compound is obtained in the formof colourless crystals having the following physico-chemical properties:melting point 77° (from methylene chloride/diethyl ether/pentane);

TLC: R_(f) =0.55 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.45, 5.6, 5.86, 6.25, 6.62, 6.72, 7.40, 7.68, 8.39,8.45, 8.53, 9.10, 9.75, 10.05 and 11.8μ; NMR spectrum (in CDCl₃ /100 Mc,in ppm): 8.06, 2H, d, J=10 Hz; 7.25, 4H, m; 6.75, 2H, d, J=10 Hz; 5.75,1H, dd, J₁ =4 Hz, J₂ =2 Hz; 5.18, 2H, AB, J=14 Hz; 3.9, 1H, dd, J₁ =16Hz, J₂ =4 Hz; 3.56, 1H, dd, J₁ =16 Hz, J₂ =2 Hz; 2.88, 6H, s.

EXAMPLE 22 (5R,S)-2-(3-Dimethylaminophenyl)-2-penem-3-carboxylic acid

3 ml of 0.2M aqueous sodium bicarbonate solution and 150 mg of 10%palladium/carbon catalyst are added to a solution of 65 mg (0.15 mmol)of (5R,S)-2-(3-dimethylaminophenyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester in 4 ml of absolute ethyl acetate and the mixture isstirred for 60 minutes at normal pressure under hydrogen. Thehydrogenated mixture is filtered off from the catalyst over diatomaceousearth, the residue is washed with 2 ml of 0.2M sodium bicarbonatesolution and ethyl acetate. The aqueous phase is separated from thefiltrate and washed with diethyl ether. The washed aqueous solution isacidifed with 5% aqueous citric acid solution and exhaustively extractedwith methylene chloride. The combined methylene chloride extracts aredried over sodium sulphate, filtered and concentrated in vacuo. Thetitle compound obtained has the following physico-chemical properties:

IR spectrum (CH₂ Cl₂); absorption bands at 3.4, 5.57, 5.77, 5.95, 6.25,6.70, 7.40, 8.08, 8.28, 8.80, 9.05 and 10.05μ.

EXAMPLE 23 (4R,S)-4-(3-Methoxycarbonylpropionylthio)-2-oxoazetidine

A solution of 1.11 g (7.48 mmol) of 1-thiosuccinic acid 4-monomethylester in 7.48 ml of 1N sodium hydroxide solution is added dropwise atroom temperature to a solution of 966 mg (7.48 mmol) of(4R,S)-4-acetoxyazetidin-2-one in 5 ml of water. The reaction solutionis adjusted to a pH of 8 by the addition of 1N sodium hydroxide solutionand exhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(9:1, 4:1 and 7:3) and yields the title compound with the followingphysico-chemical properties:

TLC: R_(f) =0.23 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂);absorption bands at 2.95, 3.40, 5.6, 5.77, 5.88, 6.95, 7.10, 7.30, 7.42,8.10, 8.30, 8.60, 9.35, 10.20, 10.55 and 11.15μ.

EXAMPLE 242-[4R,S)-4-(3-Methoxycarbonylpropionylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester.

A solution of 625 mg (2 equivalents) of 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester in 8 ml of toluene and 2 ml of dimethylformamide isadded at room temperature to 266 mg (1.23 mmol) of(4R,S)-4-(3-methoxycarbonylpropionylthio)-2-oxoazetidine. After addingfreshly dried molecular sieves A4, the mixture is stirred overnight atroom temperature under nitrogen. The molecular sieves are filtered offand the filtrate is concentrated in vacuo. The residue is dried underhigh vacuum and chromatographed over silica gel with toluene/ethylacetate (9:1, 4:1 and 7:3). After eluting the unreacted2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the title compoundwith the following physico-chemical properties is eluted:

TLC: R_(f) =0.20 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.85, 3.4, 5.65, 5.75, 5.95, 6.60, 7.45, 8.30 and9.15μ.

EXAMPLE 252-[(4R,S)-4-(3-Methoxycarbonylpropionylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 446 mg (1.05 mmol) of2-[(4R,S)-4-(3-methoxycarbonylpropionylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester in 8 ml of absolute dioxan is added to asolution of 2 g of poly-Hunig base in 7 ml of absolute dioxan. Afteradding a solution of 0.26 ml (3.5 equivalents) of thionyl chloride in 8ml of absolute dioxan, the reaction mixture is stirred for 100 minutesat room temperature under nitrogen. The poly-Hunig base is filtered offand the filtrate is concentrated in vacuo. The crude2-[(4R,S)-4-(3-methoxycarbonylpropionylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester having the following physico-chemicalproperties:

TLC: R_(f) =0.47 (toluene/ethyl acetate 1:1); IR spectrum (in CH₂ Cl₂):absorption bands at 3.40, 5.65, 5.80, 5.95, 6.60, 7.45, 7.65, 8.15,8.35, 8.50, 9.40, 10.0 and 11.4μ is used in the subsequent reactionwithout further purification.

(b) The crude2[(4R,S)-4-(3-methoxycarbonylpropionylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 25 ml of absolutedioxan, 2 g of poly-Hunig base and 433 mg of triphenylphosphine areadded and the mixture is stirred overnight at 50° under nitrogen. Thepoly-Hunig base is filtered off, washed with dioxan and the filtrate andwashing liquid are concentrated together in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and1:1) and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.1 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.40, 5.70, 5.95, 6.20, 6.60, 7.00, 7.45, 7.90,8.30, 9.05 and 9.30μ.

EXAMPLE 26 (5R,S)-2-(2-Methoxycarbonylethyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of hydroxyquinone is added to a solution of 272 mg(0.41 mmol) of2-[(4R,S)-4-(3-methoxycarbonylpropionylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 100 ml of absolute toluene and the mixtureis stirred for two days at 90° under nitrogen. The solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (19:1 and 9:1). The title compound is obtained inthe form of colourless crystals melting at 125° (from methylenechloride/diethyl ether);

TLC: R_(f) =0.47 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.30, 3.45, 5.60, 5.78, 5.85, 6.33, 6.56, 7.45,7.65, 8.35, 8.80 and 9.50μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm):8.28, 2H, d, J=9 Hz; 7.65, 2H, d, J=9 Hz; 5.70, 1H, dd, J₁ =2 Hz, J₂ =4Hz; 5.40, 2H, AB, J=14 Hz; 3.85, 1H, ABX, J₁ =16 Hz, J₂ =4 Hz; 3.74, 3H,s; 3.55, 1H, ABX, J₁ =16 Hz, J₂ =2 Hz; 3.20, 2H; 2.64, 2H.

EXAMPLE 27 (5R,S)-2-(2-Methoxycarbonylethyl)-2-penem-3-carboxylic acid

3 ml of 2M aqueous sodium bicarbonate solution and 150 mg of 10%palladium/carbon catalyst are added to a solution of 50 mg of(5R,S)-2-(2-methoxycarbonylethyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester in 3 ml of absolute ethyl acetate, and the mixtureis stirred for 60 minutes at normal pressure under hydrogen. Thehydrogenated mixture is filtered off from the catalyst over diatomaceousearth, the residue is washed with 2 ml of 2M sodium bicarbonate solutionand ethyl acetate and the aqueous phase is separated from the filtrateand washing liquid. The aqueous solution is washed once with diethylether, acidified with 5% aqueous citric acid solution and exhaustivelyextracted with methylene chloride. The combined methylene chlorideextracts are dried over sodium sulphate, filtered, concentrated in vacuoand dried under high vacuum. The title compound obtained has thefollowing physico-chemical properties:

IR spectrum (CH₂ Cl₂): 3.45, 5.57, 5.75, 5.95, 6.35, 7.0, 7.70, 8.35,8.50 and 9.50μ; UV spectrum in ethanol: λ_(max) at 262 and 304 nm.

EXAMPLE 28 (4R,S)-4-Benzoylthio-2-oxoazetidine

A solution of 5.5 g (40 mmol) of thiobenzoic acid in 40 ml of 1N sodiumhydroxide solution is added dropwise at 0° to a solution of 5.15 g (40mmol) of (4R,S)-4-acetoxyazetidin-2-one in 20 ml of water. The reactionmixture is adjusted to a pH of approximately 7 and stirred overnight.The precipitated title compound is filtered off, washed with cold wateruntil free of alkali and recrystallised from methylene chloride/hexane.

Melting point: 104°-105°; TLC: R_(f) =0.56 (toluene/ethyl acetate 1:1);IR spectrum (CH₂ Cl₂): absorption bands at 2.92, 5.57, 5.95, 6.20, 6.27,8.22, 8.45, 10.85 and 11.10μ.

EXAMPLE 29 2-[(4R,S)-4-Benzoylthio-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

Freshly dried molecular sieves are added to a solution of 2.35 g (11.38mmol) of (4R,S)-4-benzoylthio-2-oxoazetidine and 6.45 g of2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in a mixture of 120 mlof dry toluene and 30 ml of dimethylformamide and the mixture is stirredunder nitrogen overnight at room temperature and then for 2 hours at50°. The molecular sieves are filtered off and the filtrate isconcentrated in vacuo. The residue is dried under a high vacuum andchromatographed over silica gel with toluene/ethyl acetate (9:1 and3:1). After eluting the unreacted 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester, the title compound having the followingphysico-chemical properties is eluted:

TLC: R_(f) =0.56 (toluene/ethyl acetate 1:1); Ir spectrum (CH₂ Cl₂):absorption bands at 2.85, 5.6, 5.67, 5.95, 6.00, 6.52, 7.40, 8.25, 9.00,9.15, 10.00 and 11.70μ.

EXAMPLE 302-[(4R,S)-4-Benzoylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 3 g of2-[(4R,S)-4-benzoylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester in 50 ml of dioxan is added to a mixture of 10 g ofpoly-Hunig base in 50 ml of dioxan. After adding a solution of 3 ml ofthionyl chloride in 50 ml of dioxan, the reaction mixture is stirred for5 hours at room temperature. The poly-Hunig base is filtered off and thefiltrate is concentrated in vacuo.

(b) The crude 2-[(4R,S)-4-benzoylthio-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 100 ml of dioxan, 10 gof poly-Hunig base and 3.5 g of triphenylphosphine are added and themixture is stirred for 15 hours at 50°. The poly-Hunig base is filteredoff and the filtrate is concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 and 3:2)and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.28 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 5.67, 6.00, 6.15, 6.55, 7.42, 8.30, 9.05, 9.25 and11.05μ.

EXAMPLE 31 (5R,S)-2-Phenyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 2.40 g(3.63 mmol) of2-[(4R,S)-4-benzoylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 800 ml of dry toluene and the mixture isstirred for two days at 90°. The solvent is evaporated off in vacuo andthe residue is chromatographed over silica gel with toluene/ethylacetate (19:1). The title compound is obtained in the form of colourlesscrystals having the following physico-chemical properties:

melting point 182°-183° (from methylene chloride/diethyl ether);

TLC: R_(f) =0.67 (toluene/ethyl acetate 1:1); UV spectrum (ethanol):λ_(max) =258 nm (ε=17256); 327 nm (ε=8112);

IR spectrum (CH₂ Cl₂): absorption bands at 5.55, 5.82, 6.55, 7.40, 7.65,8.35, 8.45, 9.15, 9.85μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.10,d, J=9 Hz, 2H; 7.38, m, 7H; 5.78, qu, J=4 Hz, J₂ =2 Hz, 1H; 5.29, d,J=14 Hz, 1H; 5.12, J=14 Hz, 1H; 3.88, qu, J₁ =16 Hz, J₂ =4 Hz, 1H; 3.60,qu, J₁ =16 Hz, J₂ =2 Hz, 1H.

EXAMPLE 32 (5R,S)-2-Phenyl-2-penem-3-carboxylic acid

A suspension of 200 mg of (5R,S)-2-phenyl-2-penem-3-carboxylic acidp-nitrobenzyl ester in 12 ml of ethyl acetate and 8 ml of 0.2M aqueoussodium bicarbonate solution is rinsed with nitrogen, 350 mg of 10%palladium/carbon catalyst are added and the mixture is stirred at normalpressure for 1 hour and 30 minutes under hydrogen. The hydrogenatedmixture is filtered off from the catalyst over diatomaceous earth, theresidue is washed with 2 ml of water and 5 ml of ethyl acetate, and thefiltrate and washing liquid are combined. The aqueous phase isseparated, acidified with 5% aqueous citric acid solution and extractedwith methylene chloride. The organic phase is dried over sodiumsulphate, filtered, concentrated in vacuo and dried under high vacuum.The title compound obtained has the following physico-chemicalproperties:

melting point: 127°-128° (from acetone/diethyl ether);

UV spectrum (ethanol): λ_(max) =323 mμ (ε=7310); 246 mμ (sh) (ε=9570);235 mμ (ε=10470); IR spectrum (KBr): absorption bands at 3.50, 5.60,6.00, 6.45, 6.72, 6.97, 7.67, 7.85, 8.27, 9.65, 11.05, 13.10, 13.30,13.95 and 14.45μ; NMR spectrum (CDCl₃ /100 Mc, in ppm): 7.42, m, 5H;5.78, qu, J₁ =4 Hz, J₂ =2 Hz, 1H; 3.88, qu, J₁ =16 Hz, J₂ =4 Hz, 1H;3.60, qu, J₁ =16 Hz, J₂ =2 Hz, 1H.

EXAMPLE 33 (4R,S)-4-Acetoxyacetylthio-2-oxoazetidine

A precooled solution of 13.4 g (0.1 mol) of acetoxythioacetic acid in100 ml of 1N sodium hydroxide solution is added to a solution of 8.5 g(0.065 mol) of (4R,S)-4-acetoxyazetidin-2-one in 50 ml of acetone andthe mixture is stirred at room temperature for 3 hours. The reactionmixture is extracted 3 times with 100 ml of methylene chloride eachtime. The combined organic phases are dried over sodium sulphate andconcentrated in vacuo. The residue is chromatographed over silica gelwith toluene/gel acetate (4:1) and yields the title compound having thefollowing physico-chemical properties:

TLC: R_(f) =0.34 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.6, 5.72, 5.9 and 8.20μ.

The acetoxythioacetic acid used as starting material may be produced asfollows

Hydrogen sulphide is conducted through an ice-cold solution of 6.11 g(0.1 mol) of potassium hydroxide in 3 ml of water and 55 ml of ethanolfor 45 minutes. A solution of 3.73 g (0.027 mol) of acetoacetyl chloridein 20 ml of dry dioxan is added dropwise over a period of 20 minutes,while stirring, to the so-obtained ice-cold solution of potassiumhydrogen sulphide. After stirring for one hour at room temperature, thereaction mixture is extracted with diethyl ether, acidified with cooled2N sulphuric acid and extracted with diethyl ether. The organic phase isdried and concentrated and the resulting acetoxythioacetic acid is usedin the above reaction without further purification.

EXAMPLE 342-[(4R,S)-4-Acetoxyacetylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester

Freshly dried molecular sieves are added to a solution of 0.44 g (2.17mmol) of (4R,S)-acetoxyacetylthio-2-oxoazetidine and 1.23 g of2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in a mixture of 25 mlof toluene and 5 ml of dimethylformamide and the mixture is stirredunder nitrogen overnight at room temperature and then for 4 hours at50°. The molecular sieves are filtered off and the filtrate isconcentrated in vacuo. The residue is dried under high vacuum andchromatographed over silica gel with toluene/ethyl acetate (9:1 to 4:1).After eluting the unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzylester, the title compound having the following physico-chemicalproperties is eluted:

TLC: R_(f) =0.31 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.9, 5.6, 5.7, 5.90, 6.25, 6.55, 7.45 and 8.25μ.

EXAMPLE 352-[(4R,S)-4-Acetoxyacetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 0.26 ml of thionyl chloride in 5 ml of dioxan is addedto a stirred mixture of 0.82 g (2 mmol) of2-[(4R,S)-4-acetoxyacetylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester and 2 g of poly-Hunig base in 20 ml of dry dioxan.The reaction mixture is stirred for one hour at room temperature, thepoly-Hunig base is filtered off and the filtrate is concentrated invacuo.

(b) The crude2-[(4R,S)-4-acetoxyacetylthio-2-oxo-1-azetidinyl]-2-chloroacetic acidp-nitrobenzyl ester so obtained is dissolved in 20 ml of dry dioxan, 2 gof poly-Hunig base and 0.5 g of triphenylphosphine are added and themixture is stirred overnight at 50°. The poly-Hunig base is filtered offand the filtrate is concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 to 1:1)and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.15 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 5.70, 6.15, 6.55, 6.98, 7.45, 8.20, 8.85 and 9.05μ.

EXAMPLE 36 (5R,S)-Acetoxymethyl-2-penem-3-carboxylic acid p-nitrobenzylester

A catalytic amount of hydroquinone is added to a solution of 0.656 g (1mmol) of2-[(4R,S)-4-acetoxyacetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 100 ml of dry toluene and the mixture isstirred for 36 hours at 90°. The solvent is evaporated off in vacuo andthe residue is chromatographed over silica gel with toluene/ethylacetate (9:1). The title compound is obtained in the form of colourlesscrystals having the following physico-chemical properties:

melting point 127°-128° (from methylene chloride/diethyl ether);

TLC: R_(f) =0.53 (toluene/ethyl acetate 1:1); UV spectrum (ethanol):λ_(max) =319 nm (ε=9173); 262 nm (ε=11897);

IR spectrum (CH₂ Cl₂): absorption bands at 5.60, 5.75, 5.85, 6.30, 6.55,7.45, 7.60, 8.20μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 2.14, s, 3H;3.58, dd, J_(A) =16 Hz, J_(B) =2 Hz, 1H; 3.84, dd, J_(A) =16 Hz, J_(C)=4 Hz, 1H; 5.00-5.60, two overlapping AB quartets, 4H; 5.72, qu, J_(B)=2 Hz; J_(C) =4 Hz, 1H; 7.63, d, J=8 Hz, 2H; 8.22, d, J=8 Hz, 2H.

EXAMPLE 37 (5R,S)-2-Acetoxymethyl-2-penem-3-carboxylic acid

4 ml of 0.2M aqueous bicarbonate solution and 200 mg of 10%palladium/carbon catalyst are added to a solution of 100 mg (0.26 mmol)of (5R,S)-2-acetoxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl esterin 6 ml of ethyl acetate and the mixture is stirred under hydrogen atnormal pressure for 40 minutes. The hydrogenated mixture is filtered offfrom the catalyst over diatomaceous earth. The aqueous phase isacidified with 10 ml of 5% aqueous citric acid solution and extracted 3times with 20 ml of methylene chloride each time. The organic phase isdried over sodium sulphate, filtered, concentrated in vacuo and driedunder high vacuum. The title compound obtained has the followingphysico-chemical properties:

TLC: R_(f) =0.16 (toluene/ethyl acetate/acetic acid 60:40:5);

UV spectrum (ethanol): λ_(max) =312 and 247 mμ; IR spectrum (KBr):absorption bands at 3.45 b, 5,60, 5.72, 6.00, 6.40, 6.85, 7.25, 7.60,7.80, 8.20, 8.30, and 9.65μ; NMR spectrum (DMSO d6/100 Mc, in ppm):2.00, s, 3H; 3.4, dd, J_(A) =16 Hz, J_(B) =2 Hz, 1H; 3.74, dd, J_(A) =16Hz, J_(C) =4 Hz, 1H; 5.04, d, J=15 Hz, 2H; 5.63, qu, J_(B) =2 Hz, J_(C)=4 Hz, 1H.

EXAMPLE 38 (4R,S)-4-Hexanoylthio-2-oxoazetidine

A solution, prepared in the cold, of 2.64 g (20 mmol) of thiohexanoicacid in 10 ml of 2N sodium hydroxide solution is added dropwise to anice-cooled solution of 2.58 g (20 mmol) of(4R,S)-4-acetoxyazotidin-2-one in 10 ml of dioxan, and the mixture isstirred at room temperature for 30 minutes. The reaction mixture isextraced with methylene chloride. The combined organic phases are driedover sodium sulphate and concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate and yieldsthe title compound having the following physico-chemical properties:

TLC: R_(f) =0.43 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.00, 5.65 and 5.85μ.

EXAMPLE 39 2-[(4R,S)-4-Hexanoylthio-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

2.38 g (11.84 mmol) of (4R,S)-4-hexanoylthio-2-oxoazetidine and 6 g of2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are dissolved at roomtemperature in a mixture of 120 ml of toluene and 30 ml ofdimethylformamide. After adding freshly dried molecular sieves, themixture is stirred under nitrogen for 15 hours at room temperature andthen for 2 hours at 50°. The molecular sieves are filtered off, thefiltrate is concentrated in vacuo and the residue is chromatographedover silica gel with toluene/ethyl acetate (9:1 to 4:1). After elutingthe unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, thecrude title compound having the following physico-chemical properties iseluted:

TLC: R_(f) =0.47 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.85, 5.65, 5.75, 5.85, 6.25, 6.58 and 7.45μ.

EXAMPLE 402-[(4R,S)-4-Hexanoylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 6.70 g of2-[(4R,S)-4-hexanoylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester in 100 ml of dioxan is stirred with 15 g ofpoly-Hunig base, and a solution of 6 ml of thionyl chloride in 50 ml ofdioxan is added dropwise. The reaction mixture is stirred for 5 hours atroom temperature, the poly-Hunig base is filtered off and the filtrateis concentrated in vacuo.

(b) The crude2-[(4R,S)-4-hexanoylthio-2-oxo-1-azetidinyl]-2-chloroacetic acidp-nitrobenzyl ester obtained is dissolved in 150 ml of dioxan, 15 g ofpoly-Hunig base and 6 g of triphenylphosphine are added, and the mixtureis stirred overnight at 50°. The poly-Hunig base is filtered off and thefiltrate is concentrated in vacuo. The residue is chromatographed oversilica gel with toluene/ethyl acetate (9:1 to 1:1) and yields the titlecompound having the following physico-chemical properties:

TLC: R_(f) =0.33 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 5.70, 5.9, 6.15, 6.57, 6.96 7.45, 9.05 and 9.25μ.

EXAMPLE 41 (5R,S)-2-Pentyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 4.4 g (6.7mmol) of2-[(4R,S)-4-hexanoylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 2 liters of dry toluene and the mixture isstirred for 2 days at 90°. The solvent is evaporated off in vacuo andthe residue is chromatographed over silica gel with toluene/ethylacetate (19:1). The title compound having the following physico-chemicalproperties is obtained:

TLC: R_(f) =0.68 (toluene/ethyl acetate 1:1); UV spectrum (ethanol):λ_(max) =310 nm (ε=9759); 270 nm (ε=13 593);

IR spectrum (CH₂ Cl₂): absorption bands at 5.60, 5.85, 6.35, 6.57, 7.43,7.65, 8.37 and 9.05μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.20, d,J=8 Hz, 2H; 7.60, d, J=8 Hz, 2H; 5.62, qu, J_(cis) =4 Hz, J_(trans) =2Hz, 1H; 5.44, d, J=14 Hz, 1H; 5.20, d, J=14 Hz, 1H; 3.80, qu, J=16 Hz,J_(cis) =4 Hz, 1H; 3.48, qu, J=16 Hz, J_(trans) =2 Hz, 1H; 2.84, m, J=14Hz, J=7 Hz, 2H; 1.10-1.70, m, 6H; 0.88, t, 3H.

EXAMPLE 42 (5R,S)-2-Pentyl-2-penem-3-carboxylic acid

32 ml of 0.2M aqueous sodium bicarbonate solution and 1.60 g of 10%palladium/carbon catalyst are added to a solution of 800 mg (2.1 mmol)of (5R,S)-2-pentyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 48ml of ethyl acetate and the mixture is stirred at normal pressure for 60minutes under hydrogen. The hydrogenated mixture is filtered off fromthe catalyst over diatomaceous earth. The aqueous phase is acidifiedwith 80 ml of 5% aqueous citric acid solution and extracted withmethylene chloride. The organic phase is dried over sodium sulphate,filtered, concentrated in vacuo and dried under high vacuum. The titlecompound obtained is recrystallised from diethyl ether.

Melting point: 99°-100°;

UV spectrum (ethanol): λ_(max) =307 mμ (ε=5321); 257 mμ (ε=3712); Irspectrum (CH₂ Cl₂): absorption bands at 2.75-4.25 (b); 5.60, 5.97, 6.40,7.05, 7.70, 8.25, 8.32μ;

NMR spectrum (CDCl₃ /100 Mc, in ppm): 8.20 b, 1H; 5.63, qu, J_(cis) =4Hz, J_(trans) =2 Hz, 1H; 3.80, qu, J_(gem) =16 Hz, J_(cis) =4 Hz, 1H;3.46, qu, J_(gem) =16 Hz, J_(trans) =2 Hz, 1H; 283, m,J_(gem) =14 Hz,J_(H),CH.sbsb.2 =7 Hz, 2H; 1.10-1.80, m, 6H; 0.89, t, 3H.

EXAMPLE 43 (4R,S)-4-tert.-Butylthioacetylthio-2-oxoazetidine

A solution, prepared in the cold, of 5.74 g (35 mmol) oftert.-butylthiothioacetic acid in 35 ml of 1N sodium hydroxide solutionis added dropwise, while cooling, to a solution of 3.79 g (28.3 mmol) of(4R,S)-4-acetoxyazetidin-2-one in 15 ml of dioxan and the mixture isstirred for two hours at room temperature. The reaction mixture isextracted with methylene chloride. The organic phase is dried oversodium sulphate and concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 to 3:1)and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.39 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂);absorption bands at 2.97, 3.42, 5.65, 5.87, 8.62 and 10.22μ.

The thiocarboxylic acid used as starting material is obtained asfollows.

A mixture of 50 ml of pyridine and 150 ml of dry methylene chloride issaturated with hydrogen sulphide while cooling, and over a period of 30minutes a solution of 10 g (0.06 mol) of tert.-butylthioacetyl chloridein 50 ml of dry methylene chloride is added dropwise. The reactionmixture is heated to room temperature whilst passing through hydrogensulphide and is stirred for 2 hours. After acidifying with 2N sulphuricacid, the organic phase is separated, dried and concentrated in vacuo.The residue is used in the above reaction without further purification.

EXAMPLE 442-[(4R,S)-4-tert.-Butylthioacetylthio-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

Freshly dried molecular sieves are added to a solution of 4.8 g (20.5mmol) of (4R,S)-4-tert.-butylthioacetylthio-2-oxoazetidine and 11.6 g of2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in a mixture of 250 mlof dry toluene and 55 ml of dimethylformamide and the mixture is stirredfor 16 hours at room temperature and then for 2 hours at 50°. Themolecular sieves are filtered off, the filtrate is concentrated in vacuoand the residue is chromatographed over silica gel with toluene/ethylacetate(4:1). After eluting the unreacted 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester, the title compound having the followingphysico-chemical properties is eluted:

TLC: R_(f) =0.38 (toluene/ethyl acetate 1:1); IR-spectrum (CH₂ Cl₂):absorption bands at 2.85, 5.62, 5.70, 5.95, 6.22, 6.55, 7.42, 8.30, 9.25and 11.75μ.

EXAMPLE 452-[(4R,S)-4-tert.-Butylthioacetylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A mixture of 9.46 g of2-[(4R,S)-4-acetylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester, contaminated by some 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester, and 1.52 g of poly-Hunig base in 180 ml of dioxan,is stirred for 30 minutes, and a solution of 2.6 ml of thionyl chloridein 50 ml of dioxan is added. The reaction mixture is stirred for 2 hoursat room temperature, the poly-Hunig base is filtered off and thefiltrate is concentrated in vacuo.

(b) The crude2-[(4R,S)-4-tert.-butylthioacetylthio-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester so obtained is dissolved in 200 ml of dioxan,15 g of poly-Hunig base and 6.125 g of triphenylphosphine are added andthe mixture is stirred for 16 hours at 50°. The poly-Hunig base isfiltered off and the filtrate is concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 to 4:1)and yields the title compound having the following physico-chemicalproperties:

TLC: R_(f) =0.27 (toluene/ethyl acetate 1:1); IR-spectrum (CH₂ Cl₂):absorption bands at 3.40, 5.65, 5.95, 6.12, 6.55, 7.40, 8.00 and 8.20μ.

EXAMPLE 46 (5R,S)-2-tert.-Butylthiomethyl-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 2.57 g(3.75 mmol) of2-[(4R,S)-4-tert.-butylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 800 ml of dry toluene and the mixture isstirred for 17 hours at 90°. The solvent is evaporated off in vacuo andthe residue is chromatographed over silica gel with toluene/ethylacetate (9:1). The title compound is obtained by crystallisation frommethylene chloride/petroleum ether and has the followingphysico-chemical properties:

melting point 150°-152°; TLC: R_(f) =0.59 (toluene/ethyl acetate 1:1);UV spectrum (ethanol): λ_(max) =323 nm (ε=8084); 263 nm (ε=13313); IRspectrum (CH₂ Cl₂): absorption bands at 3.37, 5.60, 5.85, 6.58, 7.45,7.65, 8.45 and 8.85μ;

NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.20, d, J=8 Hz, 2H; 7.60, d,J=8 Hz, 2H; 5.61, qu, J_(cis) =4 Hz, J_(trans) =2 Hz, 1H; 5.46, d,J_(gem) =14 Hz, 1H; 5.24, d, J_(gem) =14 Hz, 1H; 4.08, d, J_(gem) =14Hz, 1H; 3.86, d, J_(gem) =14 Hz, 1H; 3.80, m, J_(gem) =16 Hz, J_(cis) =4Hz, 1H; 3.52, m, J_(gem) =16 Hz, J_(trans) =2 Hz, 1H; 1.32, s, 9H.

EXAMPLE 47 (5R,S)-2-tert.-Butylthiomethyl-2-penem-3-carboxylic acid

3.6 ml of 0.2M aqueous sodium bicarbonate solution and 183 mg of 10%palladium/carbon catalyst are added to a solution of 116 mg (0.28 mmol)of (5R,S)-2-tert.-butylthiomethyl-2-penem-3-carboxylic acidp-nitrobenzyl ester in 10 ml of ethyl acetate and the mixture is stirredat normal pressure for 60 minutes under hydrogen. The hydrogenatedmixture is filtered off from the catalyst over diatomaceous earth. Theaqueous phase is washed with diethyl ether, acidified with 5% aqueouscitric acid solution and extracted with methylene chloride. The organicphase is dried over sodium sulphate, filtered, concentrated in vacuo anddried under high vacuum. The title compound obtained has the followingphysico-chemical properties:

melting point 132°-133° (from acetone/diethyl ether);

UV spectrum (ethanol): λ_(max) =314 mμ (ε=3918); 259 mμ (3667);

IR spectrum (KBr): absorption bands at 2.95, 3.40, 3.95, 5.60, 6.02,6.47, 6.95, 7.52, 7.87, 8.20 and 14.05μ;

NMR spectrum (DMSO d6/100 Mc, in ppm): 5.62, qu, J_(cis) =4 Hz,J_(trans) =˜2 Hz, 1H; 4.20, d, J_(gem) =14 Hz, 1H; 3.83, d, J_(gem) =14Hz, 1H; 3.80, J_(gem) =16 Hz, J_(cis) =4 Hz, 1H; 3.44, qu, J_(gem) =16Hz, J_(trans) =˜2 Hz, 1H; 1.30, s, 9H.

EXAMPLE 48(4R,S)-4-(4-p-Nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidine

A solution, prepared in the cold, of 2.98 g (10 mmol) of4-p-nitrobenzyloxycarbonylaminothiobutyric acid in 10 ml of 1N sodiumhydroxide solution is added dropwise to a precooled solution of 1.1 g(8.52 mmol) of (4R,S)-4-acetoxyazetidin-2-one in 10 ml of dioxan and themixture is stirred at room temperature for 11/2 hours. The reactionmixture is exhaustively extracted with methylene chloride. The combinedorganic phases are dried over sodium sulphate and concentrated in vacuo.The residue is chromatographed over silica gel with toluene/ethylacetate (9:1, 7:2 and 1:1) and yields the title compound with thefollowing physico-chemical properties:

TLC: R_(f) =0.33 (toluene/ethyl acetate 1:2); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.65, 5.80, 5.92, 6.25, 6.60, 7.45 and 8.15μ.

The thiocarboxylic acid used as starting material is obtained asfollows:

(a) A solution of 25.87 g (0.12 mmol) of p-nitrobenzyl chloroformate in100 ml of dry dioxan is added dropwise in a period of 20 minutes to asolution of 10.30 g (0.1 mmol) of 4-aminobutyric acid in 300 ml of 1Nsodium hydroxide solution in an ice bath. The reaction mixture isstirred for 3 hours at room temperature, washed with ethyl acetate andacidified with 2N hydrochloric acid. The precipitated4-p-nitrobenzyloxycarbonylaminobutyric acid is filtered off andrecrystallised from ethyl acetate; melting point: 145°-146°.

(b) 2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol)of isobutyl chloroformate in 20 ml of dry methylene chloride are addeddropwise in succession to a solution, cooled to -10°, of 2.82 g (10mmol) of 4-p-nitrobenzyloxycarbonylaminobutyric acid in 50 ml of drymethylene chloride. The reaction mixture is stirred for one hour andsubsequently a strong current of hydrogen sulphide is passed through fora period of 2 hours. After acidifying with 2N sulphuric acid, theorganic phase is separated, dried and concentrated in vacuo. The4-p-nitrobenzyloxycarbonylaminothiobutyric acid obtained can be usedwithout further purification.

EXAMPLE 492-[(4R,S)-4-(4-p-Nitrobenzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

2.724 g (7.42 mmol) of(4R,S)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidine and4.35 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester aredissolved at room temperature in 120 ml of toluene and 30 ml ofdimethylformamide. After adding freshly dried molecular sieves themixture is stirred under nitrogen overnight at room temperature and thenfor 2 hours at 50°. The molecular sieves, are filtered off, the filtrateis concentrated in vacuo and the residue is chromatographed over silicagel with toluene/ethyl acetate (9:1, 8:1 and 1:1). After eluting theunreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the titlecompound with the following physico-chemical properties is eluted:

TLC: R_(f) =0.23 (toluene/ethyl acetate 1:2); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.65, 5.75, 5.82, 6.25, 6.60, 7.45, 8.25,9.05, 9.80 and 11.75μ.

EXAMPLE 502-[(4R,S)-4-(4-p-Nitrobenzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 4 ml of thionyl chloride in 25 ml of absolute dioxanis added dropwise at room temperature to a mixture of 3.676 (6.38 mmol)of2-[(4R,S)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester and 8 g of poly-Hunig base in 50 ml of absolutedioxan. The reaction mixture is stirred for 3 hours at room temperatureunder nitrogen, the poly-Hunig base is filtered off and the filtrate isconcentrated in vacuo.

(b) The crude2-[(4R,S)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester so obtained is dissolved in 100 ml of absolutedioxan, 9 g of poly-Hunig base and 3 g of triphenylphosphine are addedand the mixture is stirred overnight at 50° under nitrogen. Thepoly-Hunig base is filtered off and the filtrate is concentrated invacuo. The residue is chromatographed over silica gel with toluene/ethylacetate (9:1, 8:2 and 1:1) and yields the title compound with thefollowing physico-chemical properties:

IR spectrum (CH₂ Cl₂): absorption bands at 5.70, 5.80, 5.95, 6.25, 6.60,7.00, 7.45, 8.15, 8.95, 9.05 and 9.25μ.

EXAMPLE 51(5R,S)-2-(3-p-Nitrobenzyloxycarbonylaminopropyl)-2-penem-3-carboxylicacid-p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 1.50 g(1.83 mmol) of2-[(4R,S)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 500 ml of dry toluene and the mixture isstirred under nitrogen for 24 hours at 90°. The solvent is evaporated invacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (4:1). The title compound with the followingphysico-chemical properties is obtained:

TLC: R_(f) =0.43 (toluene/ethyl acetate 1:2); UV spectrum (ethanol):λ_(max) =300 nm; 264 nm; IR spectrum (CH₂ Cl₂): absorption bands at2.80, 5.55, 5.80, 6.20, 6.37, 6.55, 7.40, 7.60 and 8.35μ; NMR spectrum(in CDCl₃ /100 Mc, in ppm): 1.80, quintet, J=7 Hz, 2H; 2.80, m, 2H;3.24, qu, J=7 Hz, 2H; 3.47, dd, J₁ =16 Hz, J₂ =2 Hz; 3.82, dd, J₁ =16Hz, J₂ =4 Hz; 5.17, s, 2H; 5.18, d, J=14 Hz, 1H; 5.43, d, J=14 Hz, 1H;5.64, qu, J₁ =2 Hz, J₂ =4 Hz, 1H; 5.10-5.70, b, 1H; 7.40-8.20, m, 8H.

EXAMPLE 52 (5R,S)-2 -(3-Aminopropyl)-2-penem-3-carboxylic acid

80 mg of 10% palladium/carbon catalyst are added to a solution of 30 mg(0.055 mmol) of(5R,S)-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-2-penem-3-carboxylicacid p-nitrobenzyl ester in 3 ml of methanol and the mixture is stirredat normal pressure for 11/2 hours under hydrogen. The hydrogenatedmixture is filtered off from the catalyst over diatomaceous earth andthe filtrate is concentrated in vacuo. The title compound obtained hasthe following physico-chemical properties:

IR spectrum (KBr): absorption bands at 2.95, 3.45, 5.65, 5.85 (sh), 6.35and 7.30μ; UV spectrum (ethanol): λ_(max) =299 nm.

EXAMPLE 53(4R,S)-3-(4-p-Nitrobenzyloxycarbonylaminopropionylthio)-2-oxoazetidine

A solution, prepared in the cold, of 5.60 g (˜20 mmol) of3-p-nitrobenzyloxycarbonylaminothiopropionic acid in 20 ml of 1N sodiumhydroxide solution is added dropwise to a precooled solution of 2.2 g(17 mmol) of (4R,S)-4-acetoxyazetidin-2-one in 10 ml of dioxan and themixture is stirred at room temperature for 3 hours. The reaction mixtureis exhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(9:1 to 1:1) and yields the title compound with the followingphysico-chemical properties:

TLC: R_(f) =0.22 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.65, 5.80, 5.95, 6.60, 7.45 and 8.17μ.

The thiocarboxylic acid used as starting material is obtained as follows

(a) A solution of 21.56 g (0.1 mmol) of p-nitrobenzyl chloroformate in30 ml of dry dioxan is added dropwise over a period of 20 minutes to asolution of 8.90 g (0.1 mmol) of 3-aminopropionic acid in 100 ml of 2Nsodium hydroxide solution in an ice bath. The reaction mixture isstirred for 2 hours at room temperature and acidified with 2Nhydrochloric acid. The precipitated3-p-nitrobenzyloxycarbonylaminopropionic acid is filtered off and dried.Melting point: 97°-98° (from ethyl acetate/diethyl ether).

(b) 4.4 g (40 mmol) of triethylamine and a solution of 2.8 ml (2 mmol)of isobutyl chloroformate in 20 ml of dry methylene chloride are addeddropwise, in succession, to a solution, cooled to -10°, of 5.36 g (20mmol) of 3-p-nitrobenzyloxycarbonylaminopropionic acid in 100 ml of drymethylene chloride. The reaction mixture is stirred for one hour at-18°, then for 11/2 hours a strong current of hydrogen sulphide ispassed through and the mixture allowed to heat up to room temperature.After acidifying with 2N sulphuric acid, again in the cold, the organicphase is separated, dried and concentrated in vacuo. The3-p-nitrobenzyloxycarbonylaminothiopropionic acid obtained can be usedwithout further purification.

EXAMPLE 542-[(4R,S)-4-(3-p-Nitrobenzyloxycarbonylaminopropionylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

4.10 g (11.6 mmol) of(4R,S)-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-2-oxoazetidineand 6.5 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester aredissolved at room temperature in 120 ml of dry toluene and 50 ml of drydimethylformamide. After adding freshly dried molecular sieves, themixture is stirred under nitrogen overnight at room temperature and thenfor 2 hours at 50°. The molecular sieves are filtered off, the filtrateis concentrated in vacuo and the residue is chromatographed over silicagel with toluene/ethyl acetate (9:1 to 1:1). After eluting unreacted2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the title compoundwith the following physico-chemical properties is eluted:

TLC: R_(f) =0.23 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.65, 5.75, 5.80, 6.25, 6.55, 7.45, 8.20 and9.20μ.

EXAMPLE 552-[(4R,S)-4-(3-p-Nitrobenzyloxycarbonylaminopropionylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 6 ml of thionyl chloride in 50 ml of dry dioxan isadded dropwise at room temperature to a stirred mixture of 6.33 g (11.2mmol) of2-[(4R,S)-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester and 12 g of poly-Hunig base in 50 ml of drydioxan. The reaction mixture is stirred for 1 hour at room temperatureunder nitrogen, the poly-Hunig base is filtered off and the filtrate isconcentrated in vacuo.

(b) The crude2-[(4R,S)-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 50 ml of dry dioxan,12 g of poly-Hunig base and 4 g of triphenylphosphine are added and themixture is stirred overnight at 50° under nitrogen. The poly-Hunig baseis filtered off and the filtrate is concentrated in vacuo. The residueis chromatographed over silica gel with toluene/ethyl acetate (9:1, 8:2and 1:1) and yields the title compound with the followingphysico-chemical properties:

IR spectrum (CH₂ Cl₂): absorption bands at 2.90, 4.67, 5.77, 5.90, 6.12,6.55, 6.95, 7.40, 9.00 and 9.25μ.

EXAMPLE 56(5R,S)-2-(2-p-Nitrobenzyloxycarbonylaminoethyl)-2-penem-3-carboxylicacid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 3 g (3.7mmol) of2-[(4R,S)-4-(3-p-nitrobenzyloxycarbonylaminopropionylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 250 ml of dry toluene and the mixture isstirred under nitrogen for 24 hours at 90°. The solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (9:1 to 4:1). The title compound with thefollowing physico-chemical properties is obtained:

TLC: R_(f) =0.44 (toluene/ethyl acetate 1:1); UV spectrum (dioxan):λ_(max) =315 nm (ε=8536); 264 nm (ε=22114);

IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 5.58, 5.80, 6.22, 6.32,6.57, 7.42, 7.62 and 8.35μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm):2.80-3.60, m, 5H; 3.84, dd, J₁ =16 Hz, J₂ =4 Hz, 1H; 5.18, s, 2H; 5.22,d, J₁ =14 Hz, 1H; 5.44, d, J=14 Hz, 1H; 5.65, qu, J₂ =4 Hz, J₃ =2 Hz,1H; 7.40-8.30, m, 8H.

EXAMPLE 57 (5R,S)-2-(2-Aminoethyl)-2-penem-3-carboxylic acid

200 mg of 10% palladium/carbon catalyst are added to a solution of 90 mg(0.19 mmol) of(5R,S)-2-(2-p-nitrobenzyloxycarbonylaminoethyl)-2-penem-3-carboxylicacid p-nitrobenzyl ester in 3 ml of methanol and the mixture is stirredat normal pressure for one hour under hydrogen. The hydrogenated mixtureis filtered off from the catalyst over diatomaceous earth, the filtrateis concentrated in vacuo and the residue is washed once with diethylether. The title compound obtained has the following physico-chemicalproperties:

IR spectrum (KBr): absorption bands at 3.00, 5.67, 5.90, 6.25, 6.30 and7.30μ.

EXAMPLE 58 (4R,S)-4-(4-Benzyloxycarbonylaminobutyrylthio)-2-oxoazetidine

A solution, prepared in the cold, of 2.53 g (10 mmol) of4-benzyloxycarbonylaminothiobutyric acid in 10 ml of 1N sodium hydroxidesolution is added dropwise to a solution of 1.29 g (10 mmol) of(4R,S)-4-acetoxyazetidin-2-one in 10 ml of dioxan, and the mixture isstirred at room temperature for 20 minutes. The reaction mixture isexhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(1:1) and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.38 (toluene/ethyl acetate 1:2); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.60, 5.80, 5.90, 6.60 and 8.10μ.

The thiocarboxylic acid used as starting material is obtained asfollows:

(a) A solution of 5.16 g (0.103 mmol) of benzyl chloroformate in 100 mlof dry dioxan is added dropwise over a period of 30 minutes to asolution of 10.60 g (0.1 mmol) of 4-aminobutyric acid in 300 ml of 1Nsodium hydroxide solution in an ice bath. The reaction mixture isstirred for 30 minutes at room temperature, acidified with 2Nhydrochloric acid and extracted with methylene chloride. The organicphase is dried with sodium sulphate and concentrated in vacuo. The4-benzyloxycarbonylaminobutyric acid obtained is recrystallized fromethyl acetate, methylene chloride and hexane; melting point 61°-62°.

(b) 2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol)of isobutyl chloroformate in 20 ml of dry methylene chloride are addeddropwise, in succession, to a solution, cooled to -10°, of 2.37 g (10mmol) of 4-benzyloxycarbonylaminobutyric acid in 50 ml of dry methylenechloride. The reaction mixture is stirred for one hour at -10° and thena strong current of hydrogen sulphide is passed through for 11/2 hours.After warming to room temperature, the mixture is cooled again andacidified with 2N sulphuric acid. The organic phase is separated, driedand concentrated in vacuo. The 4-benzyloxycarbonylaminothiobutyric acidobtained can be used without further purification.

EXAMPLE 592-[(4R,S)-4-(4-Benzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester

2.60 g (8 mmol) of(4R,S)-4-(4-benzyloxycarbonylaminobutyrylthio)-2-oxoazetidine and 4.84 gof 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are dissolved atroom temperature in a mixture of 100 ml of dry toluene and 35 ml of drydimethylformamide. After adding freshly dried molecular sieves, themixture is stirred under nitrogen overnight at room temperature and thenfor 2 hours at 50°. The molecular sieves are filtered off, the filtrateis concentrated in vacuo and the residue is chromatographed over silicagel with toluene/ethyl acetate (4:1). After eluting the unreacted2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the title compoundwith the following physico-chemical properties is eluted:

TLC: R_(f) =0.38 (toluene/ethyl acetate 1:2); IR spectrum (CH₂ Cl₂):absorption bands at 2.85, 2.95, 5.60, 5.70, 5.82, 5.97, 6.22, 6.55,7.42, 8.25 and 9.15μ.

EXAMPLE 602-[(4R,S)-4-(4-Benzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 6 ml of thionyl chloride in 50 ml of dioxan is addeddropwise at room temperature to a mixture of 7 g of2-[(4R,S)-4-(4-benzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester and 15 g of poly-Hunig base in 200 ml ofdioxan. The reaction mixture is stirred for 2 hours at room temperature,the poly-Hunig base is filtered off and the filtrate is concentrated invacuo.

(b) The crude2-[(4R,S)-4-(4-benzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 150 ml of dry dioxan,15 g of poly-Hunig base and 6 g of triphenylphosphine are added and themixture is stirred overnight at 50°. The poly-Hunig base is filtered offand the filtrate is concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 to 1:1),and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.37 (toluene/ethyl acetate 1:2); IR spectrum (CH₂ Cl₂):absorption bands at 2.92, 5.70, 5.78, 5.92, 6.15, 6.60, 6.97, 7.45,8.40, 8.95, 9.05 and 9.25μ.

EXAMPLE 61(5R,S)-2-(3-Benzyloxycarbonylaminopropyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 1 g (1.29mmol) of1-[(4R,S)-4-(4-benzyloxycarbonylaminobutyrylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 500 ml of dry toluene and the mixture isstirred under nitrogen for 36 hours at 90°. The solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (4:1). The title compound with the followingphysico-chemical properties is obtained:

TLC: R_(f) =0.42 (toluene/ethyl acetate 1:1) UV spectrum (ethanol):λ_(max) =311 nm; 260 nm; IR spectrum (CH₂ Cl₂): absorption bands at2.95, 5.60, 5.85, 6.20, 7.45, 7.65, 8.10 and 8.38μ; NMR spectrum (inCDCl₃ /100 Mc, in ppm): 1.75, quintet, 2H; 2.85, m, 2H; 3.19, qu, J=7Hz, 2H; 3.40, dd, J₁ =16 Hz, J₂ =2 Hz, 1H; 3.74, dd, J₁ =16 Hz, J₂ =4Hz, 1H; 5.06, s, 2H; 5.14, d, J=14 Hz and 5.38, d, J=14 Hz, 2H; 5.60,qu, J₁ =2 Hz, J₂ =4 Hz, 1H; 7.28, s, 5H; 7.54, d, J=9 Hz, 2H; 8.12, d,J=9 Hz, 2H.

EXAMPLE 62(5R,S)-2-(3-Benzyloxycarbonylaminopropyl)-2-penem-3-carboxylic acid

200 mg of 10% palladium/carbon catalyst is added to a solution of 105 mg(0.21 mmol) of(5R,S)-2-(3-benzyloxycarbonylaminopropyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester in 6 ml of ethyl acetate and 4 ml of 0.2M sodiumbicarbonate solution, and the mixture is stirred at normal pressure forone hour under hydrogen. The hydrogenated mixture is filtered off fromthe catalyst over diatomaceous earth, the aqueous phase is separated,acidified with 5% aqueous citric acid solution and extracted withmethylene chloride. The organic phase is dried over sodium sulphate andconcentrated in vacuo. The title compound obtained has the followingphysico-chemical properties:

TLC: R_(f) =0.41 (toluene/ethyl acetate/acetic acid 60:40:5);

IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 5.60, 5.85, 6.40, 6.65and 8.10μ; UV spectrum (ethanol): λ_(max) =307 and 255 nm.

EXAMPLE 63 (4R,S)-4-[2-(2-Phenoxyacetylamino)-acetylthio]-2-oxoazetidine

A solution, prepared in the cold, of 6 g (26.6 mmol) of2-(2-phenoxyacetylamino)-thioacetic acid in 26 ml of 1N sodium hydroxidesolution is added dropwise to a precooled solution of 3.43 g (26.5 mmol)of (4R,S)-4-acetoxyazetidin-2-one in 20 ml of dioxan and the mixture isstirred at room temperature for 30 minutes. The reaction mixture isexhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(1:1) and yields the title compound with the following physico-chemicalproperties:

melting point: 114°-115° (from methylene chloride/petroleum ether);

TLC: R_(f) =0.41 (ethyl acetate): IR-spectrum (CH₂ Cl₂): absorptionbands at 2.95, 5.60, 5.90, 6.25, 6.60, 6.70, 8.10, 9.25, 9.42 and10.20μ.

The thiocarboxylic acid used as starting material is obtained asfollows.

7.4 ml (53.8 mmol) of triethylamine and a solution of 3.7 ml (26.9 mmol)of isobutyl chloroformate in 60 ml of methylene chloride are addeddropwise, in succession, to a solution, cooled to -10°, of 5.63 g (26.9mmol) of 2-(2-phenoxyacetylamino)-acetic acid in 50 ml of dry methylenechloride. The reaction mixture is stirred for 11/2 hours at -10° and atthe same temperature a current of hydrogen sulphide is passed throughfor a period of 2 hours. After warming to room temperature, the mixtureis acidified with 2N sulphuric acid, the organic phase is separated,dried and concentrated in vacuo. The 2-(2-phenoxyacetylamino)-aceticacid obtained can be used without further purification.

EXAMPLE 642-{(4R,S)-4-[2-(2-Phenoxyacetylamino)-acetylthio]-2-oxo-1-azetidinyl}-2-hydroxyaceticacid p-nitrobenzyl ester

1.40 g (4.76 mmol) of(4R,S)-4-[2-(2-phenoxyacetylamino)-acetylthio]-2-oxoazetidine and 3.2 gof 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are dissolved atroom temperature in a mixture of 60 ml of toluene and 15 ml ofdimethylformamide. After adding freshly dried molecular sieves, themixture is stirred under nitrogen overnight at room temperature and thenfor two hours at 50°. The molecular sieves are filtered off, thefiltrate is concentrated in vacuo and the residue is chromatographedover silica gel with toluene/ethyl acetate (1:2). After eluting theunreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the titlecompound with the following physico-chemical properties is eluted:

TLC: R_(f) =0.43 (ethyl acetate); IR spectrum (CH₂ Cl₂): absorptionbands at 2.95, 5.60, 5.70, 5.90, 6.25, 6.55, 7.42 and 8.20μ.

EXAMPLE 652-{(4R,S)-4-[2-(2-Phenoxyacetylamino)-acetylthio]-2-oxo-1-azetidinyl}-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 0.76 ml of thionyl chloride in 25 ml of dioxan isadded dropwise at room temperature to a mixture of 3.01 g (5.88 mmol) of2-{(4R,S)-4-[2-(2-phenoxyacetylamino)-acetylthio]-2-oxo-1-azetidinyl}-2-hydroxyaceticacid p-nitrobenzyl ester and 4.45 g of poly-Hunig base in 65 ml of drydioxan. The reaction mixture is stirred for 2 hours at room temperatureunder nitrogen, the poly-Hunig base is filtered off and the filtrate isconcentrated in vacuo.

(b) The crude2-{(4R,S)-4-[2-(2-phenoxyacetylamino)-acetylthio]-2-oxo-1-azetidinyl}-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 100 ml of dioxan, 5.62g of poly-Hunig base and 2.30 g of triphenylphosphine are added and themixture is stirred for 17 hours at 50° under nitrogen. The poly-Hunigbase is filtered off and the filtrate is concentrated in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(3:2) and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.09 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.70, 5.80, 6.20, 6.70, 6.98, 7.45, 8.40 and8.95μ.

EXAMPLE 66 (5R,S)-2-(2-Phenoxyacetylaminomethyl)-2-penem-3-carboxylicacid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 600 mg (0.8mmol) of2-{(4R,S)-4-[2-(2-phenoxyacetylamino)-acetylthio]-2-oxo-1-azetidinyl}-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 300 ml of dry toluene and the mixture isstirred under nitrogen for 17 hours at 90°. The solvent is evaporatedoff in vacuo, the residue is dissolved in methylene chloride and washedwith cold 1N sodium hydroxide solution. The organic phase is dried oversodium sulphate and concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (4:1). Thetitle compound with the following physico-chemical properties isobtained:

melting point: 163°-165° (methylene chloride/petroleum ether);

TLC: R_(f) =0.35 (toluene/ethyl acetate 1:1); UV spectrum (dioxan):λ_(max) =318 nm (ε=10019); 272 nm (sh) (ε=12684), 266 nm (ε=14869); 261nm (ε=14869); IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 5.55,5.85, 5.90, 6.30, 6.55, 6.70, 7.40, 7.60, 8.10, 8.25, 8.65 and 9.40μ;NMR spectrum (in CDCl₃ /100 Mc, in ppm): 3.44, dd, J₁ =16 Hz, J₂ =2 Hz,1H; 3.84, dd, J₁ =16 Hz, J₃ =4 Hz, 1H; 4.52, s, 2H; 4.34-4.80, m, 2H;5.22, d, J=14 Hz, 1H; 5.44, d, J=14 Hz, 1H; 4.66, qu, J₂ =2 Hz, J₃ =4Hz, 1H; 6.80-8.30, m, 10H.

EXAMPLE 67 (5R,S)-2-(2-Phenoxyacetylaminomethyl)-2-penem-3-carboxylicacid

135 mg of 10% palladium/carbon catalyst is added to a solution of 100 mg(0.21 mmol) of(5R,S)-2-(2-phenoxyacetylaminomethyl)-2-penem-3-carboxylic acidp-nitrobenzyl ester in 10 ml of ethyl acetate and 2.7 ml of 0.2N sodiumbicarbonate solution and the mixture is stirred at normal pressure for45 minutes under hydrogen. The hydrogenated mixture is filtered off fromthe catalyst over diatomaceous earth. The aqueous phase is separated,acidified with 5% citric acid solution and extracted with methylenechloride. The combined methylene chloride phases are dried over sodiumsulphate and concentrated in vacuo. The title compound obtained has thefollowing physico-chemical properties:

TLC: R_(f) =0.08 (toluene/ethyl acetate/acetic acid 60:40:5);

IR spectrum (methylene chloride): absorption bands at 2.8-3.60 (b),5.55, 5.75, 5.85, 6.25, 6.55, 6.70 and 8.10μ.

EXAMPLE 68 (4R,S)-4-Ethylthiothiocarbonylthio-2-oxoazetidine

A solution of 2.25 g of potassium ethyltrithiocarbonate in 12 ml ofwater is added dropwise at room temperature, under a nitrogenatmosphere, to a solution of 1.32 g of (4R,S)-4-acetoxyazetidin-2-one in3.5 ml of water and 1 ml of acetone and the mixture is stirred at thesame temperature for 30 minutes. The reaction mixture is exhaustivelyextracted with methylene chloride, the combined organic phases arewashed with saturated, aqueous sodium chloride solution, dried oversodium sulphate and concentrated in vacuo. The residue is recrystallizedfrom diethyl ether and yields the title compound in the form of yellowneedles.

Melting point: 99.5°-101.5°; TLC: R_(f) =0.315 (toluene/ethyl acetate2:3); IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 5.6, 8.12, 9.15and 9.3μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 6.85, 1H, m (exchangewith D₂ O); 5.55, 1H, m; 3.35, 2H, q; 3.6-2.9, 2H, m; 1.35, 3H, t.

EXAMPLE 692-[(4R,S)-4-Ethylthiothiocarbonylthio-2-oxo-1-azetidinyl]-2-hydroxyacetic acid-p-nitrobenzyl ester

1.7 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester is added atroom temperature to a solution of 621 mg (3 mmol) of(4R,S)-4-ethylthiothiocarbonylthio-3-oxoazetidine in 35 ml of tolueneand 9 ml of dimethylformamide. After adding freshly dried molecularsieves, the mixture is stirred under nitrogen for 15 hours at roomtemperature and then for 2 hours at 50°. The molecular sieves arefiltered off, washed with toluene and the filtrate and washing liquidare evaporated together in vacuo. The residue is dried under high vacuumand chromatographed over 80 g of silica gel with toluene/ethyl acetate(9:1). The title compound with the following physico-chemical propertiesis obtained:

TLC: R_(f) =0.26 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.62, 5.7, 6.55 and 7.45μ; NMR spectrum (in CDCl₃/100 Mc, in ppm): 8.3-8.15, 2H, m; 7.6-7.45, 2H, m; 6.1-5.9, 1H, m;5.55, 1H, d; 5.4-5.3, 2H, m; 4.2-4, 1H, m (exchange with D₂ O); 3.8-3,4H, m; 1.35, 3H, t.

EXAMPLE 702-[(4R,S)-4-Ethylthiothiocarbonylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 1.1 g of2-[(4R,S)-ethylthiothiocarbonylthio-2-oxo-1-azetidinyl]-2-hydroxyaceticacid p-nitrobenzyl ester in 23 ml of absolute dioxan is added to asolution of 4.55 g of poly-Hunig base in 11 ml of absolute dioxan thathas already been stirred for 30 minutes. After adding dropwise asolution of 0.8 ml of thionyl chloride, the reaction mixture is stirredfor 3 hours at room temperature under nitrogen. The poly-Hunig base isfiltered off, washed with dioxan and the filtrate is concentrated invacuo. The crude2-[(4R,S)-4-ethylthiothiocarbonylthio-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained can be used in the next stage withoutfurther purification.

(b) The crude2[(4R,S)-4-ethylthiothiocarbonylthio-2-oxo-1-azetidinyl]-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 54 ml of absolutedioxan, 4.55 g of poly-Hunig base and then 1.42 g of triphenylphosphineare added and the mixture is stirred for 15 hours at 50° under nitrogen.The poly-Hunig base is filtered off, washed with dioxan and the filtrateand washing liquid are concentrated together in vacuo. The residue ischromatographed over 60 g of silica gel with toluene/ethyl acetate (7:3)and yields the title compound with the following physico-chemicalproperties:

TLC: R_(f) =0.43 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.67, 6.15, 6.57, 6.97, 7.43 and 9.05μ.

EXAMPLE 71 (5R,S)-2-Ethylthio-2-penem-3-carboxylic acid p-nitrobenzylester

A solution of 9.8 g (14.85 mmol) of2[(4R,S)-4-ethylthiothiocarbonylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 3 l of dry o-xylene is stirred under refluxfor 10 hours under nitrogen. The solvent is evaporated off in vacuo andthe residue is chromatographed over 400 g of silica gel withtoluene/ethyl acetate (19:1 and then 9:1). The title compound isobtained in the form of colourless crystals by crystallisation fromdiethyl ether/methylene chloride;

melting point: 133°-134° C.; TLC: R_(f) =0.69 (toluene/ethyl acetate2:3); IR spectrum (CH₂ Cl₂): absorption bands at 5.57, 5.9, 6.22, 6.55,6.65, 7.42, 7.55, 8.37, 9.0 and 9.7μ;

NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.25-8.15, 2H, m; 7.65-7.55,2H, m; 5.7, 1H, m; 5.32, 2H, m(AB); 3.9-3.4, 2H, m; 3.1-2.8, 2H, m;2.3-1.5, 3H, t.

The reaction may alternatively be carried out in boiling toluene, thereaction time of course being prolonged to 120 hours. If desired, acatalytic amount of hydroquinone can be added to the reaction solution.

EXAMPLE 72 (5R,S)-2-Ethylthio-2-penem-3-carboxylic acid

40 ml of 0.2M aqueous sodium bicarbonate solution and 2 g of 10%palladium/carbon catalyst are added to a solution of 1 g (2.73 mmol) of(5R,S)-2-ethylthio-2-penem-3-carboxylic acid p-nitrobenzyl ester in 70ml of absolute ethyl acetate and the mixture is stirred at normalpressure for 50 minutes under hydrogen. The hydrogenated mixture isfiltered off from the catalyst over diatomaceous earth, the residue iswashed with 0.2N sodium bicarbonate solution and washed several timeswith ethyl acetate. The aqueous phase is washed with methylene chloride,acidified with 5% aqueous citric acid solution and exhaustivelyextracted with methylene chloride. The combined organic phases are driedover sodium sulphate, filtered, concentrated in vacuo, and dried underhigh vacuum. The title compound obtained has the followingphysico-chemical properties:

melting point: 143°-145° (from diethyl ether/acetone);

TLC: R_(f) =0.27 (toluene/ethyl acetate/acetic acid 60:40:5);

IR spectrum (KBr): absorption bands at 3.6-3.3, 5.6, 6.0, 6.75, 6.97,7.5, 7.9, 8.15 and 8.8μ; NMR spectrum (DMSO d6/100 Mc, in ppm): 5.75,1H, m; 4-3.3, 2H, m; 3.1-2.8, 2H, m; 1.4-1.2, 3H, t.

EXAMPLE 73 (4R,S)-4-(cis-2-Methoxycarbonylvinylthio)-azetidin-2-one

2 ml of precooled 1N sodium hydroxide solution are slowly added to asolution, cooled to -15° to -10°, of 206 mg (1.05 mmol) ofcis-2-methoxycarbonylvinylisothiouronium hydrochloride (E. G. Kako etal., J. Org. Chem. USSR. 1969, 610, English edition) in 2 ml ofmethanol, and then, at approximately -12°, 130 mg (1 mmol) of(4R,S)-4-acetoxyazetidin-2-one dissolved in 1 ml of methanol are slowlyadded. The reaction mixture is stirred for 30 minutes at -10°, dilutedwith water, saturated with common salt and extracted with ethyl acetate.The combined ethyl acetate extracts are dried with sodium sulphate andconcentrated in vacuo. The residue is chromatographed over silica gelwith toluene/ethyl acetate (2:1) and yields the title compound, whichafter recrystallisation from hot benzene has a melting point of 92°-93°.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.6, 5.9, 6.3, 8.2 and8.5μ.

EXAMPLE 742-[(4R,S)-4-(cis-2-methoxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester

1.66 g (12.5 mmol) of glyoxylic acid acetonyl ester and 15 g of welldried molecular sieves A4 are added to a solution of 936 mg (5 mmol) of(4R,S)-4-(cis-2-methoxycarbonylvinylthioazetidin-2-one in 5 ml of drydimethylformamide and 10 ml of xylene and the mixture is stirredovernight at room temperature. The molecular sieves are filtered off andwashed with 30 ml of dry tetrahydrofuran. The filtrate and washingliquid are concentrated together in vacuo, and the residue is evaporateda few times again in a vacuum of less than 0.01 mm Hg at 80° withxylene. The amorphous title compound obtained has in the IR spectrum(CH₂ Cl₂) absorption bands 5.6, 5.75, 5.85, 6.8 and 7.3μ.

The glyoxylic acid acetonyl ester is produced as follows.

(a) 35 ml of chloroacetone is slowly added to a suspension of 32 g ofdisodium fumarate in 300 ml of dry dimethylformamide and the mixture isthen stirred overnight at 100°. The reaction mixture is cooled, 1.52 lof methylene chloride is added and washing is carried out with 1Nhydrochloric acid and water. The organic phase is dried over sodiumsulphate, concentrated in vacuo and freed from the rest of the solventunder high vacuum. The fumaric acid diacetonyl ester obtained isrecrystallised from methylene chloride/diethyl ether. Melting point:121°-123°.

(b) A solution of 22.8 g of fumaric acid diacetonyl ester in 400 ml ofmethylene chloride and 200 ml of methanol is ozonised at -15° forapproximately 9 hours until no more starting material can be detected.100 ml of dimethyl sulphide is added to the ozonised mixture which isallowed to stand overnight at room temperature. Evaporation of thesolvent in vacuo and distillation of the residue at 70°-80°/0.05 mm Hgyields the glyoxylic acid acetonyl ester.

EXAMPLE 752-[(4R,S)-4-(cis-2-Methoxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester

While stirring, 0.43 ml (6 mmol) of thionyl chloride and subsequently,over a period of 5 minutes, a solution of 0.83 ml (6 mmol) oftriethylamine in 2 ml of dry tetrahydrofuran are added to a solution,cooled to -15°, of 1.7 g of2-[(4R,S)-4-(cis-2-methoxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester in 25 ml of dry tetrahydrofuran. The reactionmixture is stirred for a further 15 minutes at 0°, 150 ml of coldmethylene chloride are added and washing is carried out withhydrochloric acid/ice water. The organic phase is dried over sodiumsulphate and concentrated in vacuo. The residue is chromatographed over60 g of silica gel with toluene/ethyl acetate 1:1 and yields the titlecompound.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.6, 5.75, 5.85, 7.3, 8.15and 8.5μ.

EXAMPLE 762-[(4R,S)-4-(cis-2-Methoxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester

1.73 g (6.6 mmol) of triphenylphosphine is added to a solution of 1.15 g(3.3 mmol) of2-[(4R,S)-4-(cis-2-methoxycarbonylvinylthio)-3-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester in 3 ml of dry tetrahydrofuran and the mixture isallowed to stand at room temperature for 15 hours in a nitrogenatmosphere. The reaction mixture is diluted with 50 ml of methylenechloride, washed with cold, saturated aqueous sodium bicarbonatesolution, dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over 40 g of silica gel with toluene/ethylacetate (1:1) and yields the title compound.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.65, 5.85, 6.1 and 6.3μ.

EXAMPLE 77 (5R,S)-2-Penem-3-carboxylic acid acetonyl ester

1 ml of trifluoroacetic acid is added at -20° to a solution of 1.15 g (2mmol) of2-[(4R,S)-(cis-2-methoxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester in 30 ml of dry methylene chloride, whereupon anozone/oxygen current (0.33 mmol O₃ /minute) is passed through for aperiod of 10 minutes. The ozonised solution is rinsed with nitrogen, 1.5ml of dimethyl sulphide is added, and, after warming to roomtemperature, the mixture is shaken with 30 ml of methylene chloride and60 ml of cold, saturated, aqueous sodium bicarbonate solution. Theorganic phase is separated off, washed again with 20 ml of cold,saturated, aqueous sodium bicarbonat solution, dried over sodiumsulphate and concentrated in vacuo. The colourless foam, containing the2-[(4R,S)-4-formylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester, is dried under high vacuum, heated under reflux for30 minutes in 50 ml of dry acid-free methylene chloride and freed ofsolvent in vacuo. The residue is chromatographed over 20 g of silica gelwith toluene/ethyl acetate (1:1) and yields the title compound. A samplerecrystallised from methylene chloride/diethyl ether has a melting pointof 115°-116°.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.55, 5.75 (sh); 5.8 and6.4μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 2.2, 3H, s; 3.7, 2H, m;4.8, 2H, s; 5.8, 1H, m; 7.4, 1H, s.

EXAMPLE 78 (5R,S)-2-Penem-3-carboxylic acid

1 ml of 0.1N aqueous sodium hydroxide solution is added at 0° over aperiod of 30 minutes to a solution of 23 mg (0.1 mmol) of(5R,S)-2-penem-3-carboxylic acid acetonyl ester in 3 ml oftetrahydrofuran and the mixture is stirred for 15 minutes at the sametemperature. The reaction mixture is washed with 2 ml of diethyl etherand shaken with 20 ml of methylene chloride and 0.5 ml of 20% aqueouscitric acid. The organic phase is dried over sodium sulphate andconcentrated in vacuo. The residue is digested with methylene chlorideand the crystals are filtered off.

Melting point: 230°; TLC: R_(f) =0.3 (acetic acid/toluene/water 5:5:1):IR spectrum (in KBr): absorption bands at 5.6, 5.95, 6.45, 6.9 and12.2μ; NMR spectrum (in DMSO d6/100 Mc, in ppm): 3.7, 2H, m; 5.8, 1H, m;7.6, 1H, s.

EXAMPLE 79 (4R,S)-, (4R)- and(4S)-4-[cis-2-(1)-menthyloxycarbonylvinylthio]-azetidin-2-one

2 ml of 1N aqueous sodium hydroxide solution and then 130 mg (1 mmol) of(4R,S)-4-acetoxyazetidin-2-one dissolved in 2 ml of ethanol are slowlyadded to a solution, cooled to -10°, or 321 mg (1 mmol) ofcis-2-(1)-menthyloxycarbonylvinylisothiouronium hydrochloride in 4 ml ofethanol. The reaction mixture is stirred for 15 minutes at -10° and for15 minutes at room temperature and extracted with methylene chloride.The organic phase is dried over sodium sulphate and concentrated invacuo. The residue is chromatographed over 10 g of silica gel withtoluene/ethyl acetate (2:1) and yields the (4R,S)-title compound incrystalline form.

The pure (4S)-isomer is obtained by recrystallising the (4R,S)-compoundfrom methylene chloride/pentane at 0°. Further quantities of this isomercan be obtained by recrystallisation of the mother liquor from methanolat -70°.

Melting point: 134-135°; [α]_(D) ²⁰ =-82°±0.2°(c=1%; CHCl₃);

TLC: R_(f) =0.2 (toluene/ethyl acetate 1:1); IR spectrum (in CH₂ Cl₂):absorption bands at 2.95, 3.4, 5.6, 5.9, 8.2 and 8.5μ.

The pure (4R)-isomer is obtained from the combined mother liquors byrepeated (6 times) recrystallisation from methanol at -70° and finallyfrom methylene chloride/pentane at 0°. Melting point: 139°-141°; [α]_(D)²⁰ =-91°±1°(c=1%; CHCl₃).

The isothiouronium salt used is produced as follows:

(a) 8 drops of concentrated sulphuric acid are added to a solution of62.4 g of (1)-methanol and 42 g of propiolic acid in 120 ml of benzene,and the mixture is boiled under reflux in a water separator for 21/2days. After separating approximately 9.5 ml of water, the benzenesolution is diluted with 120 ml of benzene, washed in succession withsaturate aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over sodium sulphate and concentrated invacuo. The faintly-yellow residue is chromatographed over 1 kg of silicagel with toluene/ethyl acetate (19:1) and yields the propiolic acid(1)-methyl ester;

melting point 90°-92° C.; [α]_(D) ²⁰ =-82°±1° (c=1%; CHCl₃).

(b) A solution of 0.76 g (10 mmol) of thiourea in a mixture of 5 ml of2N hydrochloric acid and 5 ml of ethanol is slowly added to a solutionof 2.04 g (10 mmol) of propiolic acid (1-menthyl ester in 10 ml ofethanol so that the temperature does not exceed 40°. The reactionmixture is stirred at room temperature until clear and concentrated invacuo. The residue is washed with acetone on a glass suction filter,recrystallised from hot water and the crystals obtained after filtrationare washed with acetone. A sample, recrystallised from isopropanol, ofthe cis-(1)-menthyloxycarbonylvinylisothiouronium hydrochloride obtainedhas a melting point of 176°-179°; [α]_(D) ²⁰ =-74°±1° (c=1%; ethanol).

EXAMPLE 80 (4S)- and(4R)-4-[trans-2-(1)-methyloxycarbonylvinylthio]-azetidin-2-one

A solution of 64 mg (0.2 mmol) of(4S)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-azetidin-2-one in 1.5 mlof octane is refluxed at a bath temperature of 150° for 90 minutes.Chromatography over silica gel of the cis-trans-(1:4)-isomeric mixtureobtained yields the quicker running trans-isomer; [α]_(D) ²⁰ =-159°±1°(c=1%; CHCl₃); TLC: R_(f) =0.4 (toluene/ethyl acetate 1:1); IR spectrum(in CH₂ Cl₂): absorption bands at 2.95, 3.4, 5.6, 5.85, 6.25 and 8.5μ.

Using (4R)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-azetidin-2-one asthe starting material,(4R)-4-(trans-2-(1)-menthyl-oxycarbonylvinylthio)-azetidin-2-one isobtained in the same manner.

[α]_(D) ²⁰ =+26°±1° (c=1%; CHCl₃); TLC: R_(f) =0.4 (toluene/ethylacetate 1:1); IR spectrum (in CHCl₃): absorption bands at 2.95, 3.4,5.6, 5.85, 6.25 and 8.5μ.

EXAMPLE 812-[(4S)-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester

12 g of molecular sieves A4 are added to a mixture of 935 mg (3 mmol) of(4S)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-azetidin-2-one and 1 g(7.5 mmol) of glyoxylic acid acetonyl ester in 3 ml of drydimethylformamide and 6 ml of toluene, and the mixture is stirredovernight at room temperature. The molecular sieves are filtered off,washed with dry tetrahydrofuran and the filtrate and washing liquid areconcentrated together in vacuo and dried under high vacuum at 70°. Theresidue is evaporated several times in vacuo with xylene, and is used inthe subsequent reaction without further purification.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.6, 5.75, 5.9, 6.3, 8.15and 8.5μ.

EXAMPLE 822-[(4R)-(cis)-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester

Using (4R)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-azetidin-2-one asstarting material, the (4R)-isomer is obtained in a manner analogous tothat in Example 81.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.6, 5.75, 5.9, 6.3, 8.15and 8.5μ.

EXAMPLE 832-[(4S)-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester

Using (4S)-4-(trans-2-(1)-menthyloxycarbonylvinylthio)-azetidin-2-one asstarting material, the (4S)-trans-isomer is produced in a manneranalogous to that in Example 81. IR spectrum: the same absorption bandsas in Example 82.

EXAMPLE 842-[(4R)-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester

Using (4R)-4-(trans-2-(1-menthyloxycarbonylvinylthio)-azetidinone asstarting material, the (4R)-trans-isomer is produced in a manneranalogous to that in Example 81. IR spectrum: the same absorption bandsas in Example 82.

EXAMPLE 852-[(4S)-4-(cis-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester

While stirring, 0.26 ml (3.6 mmol) of thionyl chloride and, over aperiod of 5 minutes, a solution of 0.5 ml (3.6 mmol) of triethylamine in1.5 ml of tetrahydrofuran, are added to a solution, cooled to -15°, of1.54 g of2-[(4S)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester in 15 ml of dry tetrahydrofuran. The reactionmixture is stirred for a further 15 minutes at 0°, 100 ml of coldmethylene chloride are added and the mixture is washed with 30 ml ofice-cold aqueous hyrochloric acid. The organic phase is dried oversodium sulphate and concentrated in vacuo. The residue ischromatographed over 40 g of silica gel with toluene/ethyl acetate (1:1)and yields the title compound.

IR spectrum (in CH₂ Cl₂): absorption bands at 3.4, 5.6, 5.75, 5.9, 6.3,8.2 and 8.5μ.

EXAMPLE 862-[(4R)-4-(cis-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester

Using2-[(4R)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester as starting material, the (4R)-isomer is produced ina manner analogous to that in Example 85.

IR spectrum (in CH₂ Cl₂): absorption bands at 3.4, 5.6, 5.75, 5.9, 6.3,8.2 and 8.5μ.

EXAMPLE 872-[(4S)-4-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester

Using2-[(4S)-4-(trans-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester as starting material, the (4S)-trans-isomer isproduced in a manner analogous to that in Example 85.

IR spectrum (in CH₂ Cl₂): absorption bands at 3.4, 5.6, 5.75, 5.9, 6.3,8.2 and 8.5μ.

EXAMPLE 882-[(4R)-4-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester

Using2-[(4R)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-hydroxyaceticacid acetonyl ester as starting material, the (4R)-trans-isomer isproduced in a manner analogous to that in Example 85.

IR spectrum (in CH₂ Cl₂): absorption bands at 3.4, 5.6, 5.75, 5.9, 6.3,8.2 and 8.5μ.

EXAMPLE 892-[(4S)-4-(cis-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester

1.57 g (6 mmol) of triphenylphosphine is added to a solution of 1.40 g(3.3 mmol) of2-[(4S)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester in 2.5 ml of dry tetrahydrofuran, and the mixture isallowed to stand at room temperature for 24 hours in a nitrogenatmosphere. The reaction mixture is diluted with 50 ml of methylenechloride, washed with 20 ml of cold, saturated, aqueous sodiumbicarbonate solution, dried over sodium sulphate and concentrated invacuo. The residue is chromatographed over 40 g of silica gel withtoluene/ethyl acetate (1:1 and 1:2) and yields the title compound, whichis contaminated with approximately 10% of the quicker-runningcorresponding trans-compound.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.7, 5.9, 6.15 and 6.85μ;NMR spectrum (in CDCl₃ /100 Mc, in ppm): 5.9, d, 1H, J=10 Hz(ROOC--CH═).

EXAMPLE 902-[(4R)-4-(cis-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester

Using2-[(4R)-4-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester as starting material, the (4R)-cis-isomer isproduced in a manner analogous to that in Example 89.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.7, 5.9, 6.15 and 6.85μ;NMR spectrum: the same bands as in Example 89.

EXAMPLE 912-[(4S)-4-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester

Using2-[(4S)-4-(trans-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester as starting material, the (2S)-trans-isomer isproduced in a manner analogous to that in Example 89.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.7, 5.9, 6.15 and 6.85μ;NMR spectrum (in CDCl₃ /100 Mc, in ppm): 5.8, d, 1H, J=15 Hz(ROOC--CH═).

EXAMPLE 922-[(4R)-4-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester

Using2-[(4R)-4-(trans-2-(1)-Menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-chloroaceticacid acetonyl ester as starting material, the (4R)-trans-isomer isproduced in a manner analogous to that in Example 89.

IR spectrum (in CH₂ Cl₂) absorption bands at 5.7, 5.9, 6.15 and 6.85μ;NMR spectrum: the same bands as in Example 91.

EXAMPLE 93 (5S)-2-Penem-3-carboxylic acid acetonyl ester

1 ml of trifluoroacetic acid is added at -20° to a solution of 1.38 g (2mmol) of2-[(4S)-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester in 30 ml of dry methylene chloride, whereupon anozone/oxygen current (0.33 mmol O₃ /minute) is passed through for aperiod of 10 minutes. The ozonised solution is rinsed with nitrogen, 1.5ml of dimethyl sulphide is added, and after warming to room temperaturethe mixture is shaken with 30 ml of methylene chloride and 60 ml ofcold, saturated, aqueous sodium bicarbonate solution. The organic phaseis separated, washed again with 15 ml of cold, saturated, aqueous sodiumbicarbonate solution, dried over sodium sulphate and concentrated invacuo. The colourless foam, containing the2-[(4S)-4-formylthio-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester, is dried under high vacuum, heated under reflux inan argon atmosphere in 50 ml of dry, acid-free methylene chloride for 75minutes and freed of solvent in vacuo. The residue is chromatographedover 20 g of silica gel with toluene/ethyl acetate (3:1) and yields thetitle compound, which, recrystallized from methylene chloride/diethylether/pentane, has a melting point of 105° -107°.

IR spectrum (in CH₂ Cl₂): absorption bands at 5.55, 5.75 (sh), 5.8, 6.4,8.25 and 8.5μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 2.2, 3H, s; 3.7,2H, m; 4.8, 2H, s; 5.8, 1H, m; 7.4, 1H, s, [α]_(D) ²⁰ =-249°±0.5° (c=1%,CHCl₃).

The same compound is obtained if2-[(4S)-(trans-2-(1)-menthyloxycarbonylvinylthio)-2oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester is reacted in an analogous manner.

EXAMPLE 94 (5R)-2-Penem-3-carboxylic acid acetonyl ester

Using2-[(4R)-(cis-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester as starting material, the (5R)-title compound isproduced in a manner analogous to that in Example 93.

Melting point 93°-94°; IR spectrum (in CH₂ Cl₂): absorption bands at5.55, 5.8, 6.4, 8.25 and 8.5μ;

NMR spectrum (in CDCl₃ /100 Mc, in ppm): 2.2, 3H, s; 3.7, 2H, m; 4.8,2H, s; 5.8, 1H, m; 7.4, 1H, s; [α]_(D) ²⁰ =+251°±1° (c=1%, CHCl₃).

The same compound is obtained if the2-[(4R)-(trans-2-(1)-menthyloxycarbonylvinylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid acetonyl ester is reacted in a similar manner.

EXAMPLE 95 (5S)-2-Penem-3-carboxylic acid

4 ml of 0.1N aqueous sodium hydroxide solution is added dropwise at 0°in a period of 15 minutes to a solution of 91 mg (0.4 mmol) of(5S)-2-penem-3-carboxylic acid acetonyl ester in 9 ml of tetrahydrofuranand 1 ml of water and the mixture is stirred for a further 30 minutes atthe same temperature. The reaction mixture is diluted with 4 ml ofwater, washed with 8 ml of diethyl ether and shaken with 80 ml ofmethylene chloride and 2 ml of 20% aqueous citric acid. The organicphase is dried over sodium sulphate and concentrated in vacuo. Theresidue is chromatographed over 4 g of silica gel with methylenechloride/glacial acetic acid (9:1). The fractions containing the titlecompound are evaporated under high vacuum together with toluene andyield the crystalline product having a melting point of >300°; IRspectrum (in CH₂ Cl₂): absorption bands at 5.55, 5.9 and 6.4μ;[α]_(D).sup.° =-383° (c=1%, CH₂ Cl₂).

EXAMPLE 96 (5R)-2-Penem-3-carboxylic acid

Using (5R)-2-penem-3-carboxylic acid acetonyl ester as startingmaterial, the (5R)-title compound is obtained in a manner analogous tothat in Example 95.

Melting point: >300°; IR spectrum (in CH₂ Cl₂): absorption bands at5.55, 5.9 and 6.4μ; [α]_(D) ²⁰ =+384°±1° (c=1%, CH₂ Cl₂).

EXAMPLE 97 Penicillanic acid methyl ester 1-oxide

A solution of 6.5 g of penicillanic acid methyl ester (produced bycatalytic hydrogenation of 6α-bromopenicillanic acid methyl ester bymeans of 5% palladium/barium carbonate catalyst in aqueous dioxan) in220 ml of methylene chloride is cooled to -15° under nitrogen, asolution of 6.14 g of 18% m-chloroperbenzoic acid (30.23 mmol) in 140 mlof methylene chloride is added dropwise and the mixture is stirred for 2hours at the same temperature. The reaction mixture is diluted withmethylene chloride, washed in succession with 3% aqueous sodiumbisulphite solution and 8% aqueous sodium bicarbonate solution, anddried over sodium sulphate. The solvent is evaporated off in vacuo andthe residue is used in the subsequent reaction in this crude form. Asample is chroatographed over silica gel (10% H₂ O). With toluene/ethylacetate (2:1) the title compound is obtained in the form of an oil,which after repeating the purification by thin layer chromatography oversilica gel plates with toluene/ethyl acetate (1:1) has the followingphysico-chemical properties:

[απ_(D) ²⁰ =+280°±1° (c=1.005% in CHCl₃); IR spectrum (in methylenechloride); characteristic absorption bands at 3.25-3.50, 5.61, 5.72,6.86, 7.00, 7.10 (sh), 7.21, 7.32, 7.42, 7.81-8.01 (broad), 8.22 (sh),8.30-8.36, 8.47 (sh), 9.21, 9.46, 9.88 (sh) and 9.96μ; NMR spectrum (inCDCl₃ /100 Mc, in ppm): 1.23, 3H, s; 1.70, 3H, s; 3,34, 2H, d; 3.80, 3H,s; 4.51, 1H, s; 4.97, 1H, t.

EXAMPLE 982-[(4R)-4-(Benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylenebutyricacid methyl ester

A solution of 685 mg of penicillanic acid methyl ester 1-oxide and 496mg (2.97 mmol) of 2-mercaptobenzthiazole in 30 ml of toluene is heatedunder reflux for 2.5 hours. The solvent is distilled off in vacuo andthe residue is chromatographed over 60 g of silica gel. The titlecompound is obtained in amorphous form by elution with toluene/ethylacetate (9:1).

TLC: R_(f) =0.47 (ethyl acetate/toluene 1:1); IR spectrum (in methylenechloride): absorption bands at 5.66, 5.75, 5.97-6.05, 6.75 (sh), 6.84,7.03, 7.28, 7.53, 7.60 (sh), 7.65 (sh); 8.10, 8.35, 8.50, 8.89, 9.25,9.81 and 9.93μ; [α]_(D) ²⁰ =-392°±1° (c=0.777% in CHCl₃).

EXAMPLE 992-[(4R)-4-(Benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester

5 ml of triethylamine are added to a solution of 12 g of2-[(4R)-4-(benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylenebutyricacid methyl ester in 500 ml of methylene chloride and the mixture isallowed to stand at room temperature for 90 minutes. The reactionmixture is washed with 5% aqueous citric acid solution, dried oversodium sulphate and freed of solvent in vacuo. The residue is purifiedby chromatography over silica gel (deactivated with 10% water) withtoluene and toluene/ethyl acetate (19:1) and yields the title compound,which after recrystallization from diethyl ether/pentane has a meltingpoint of 63°-66°.

TLC: R_(f) =0.44 (ethyl acetate/toluene 1:1); IR spectrum (in methylenechloride): characteristic absorption bands at 3.35-3.60, 5.66, 5.81,5.87 (sh), 5.93 (sh), 6.15, 6.85, 7.04, 7.26, 7.36, 7.65 (sh), 7.73,8.17, 8.25 (sh), 8.35 (sh), 8.90, 9.18 (sh), 9.26, 9.42 (sh), 9.81 (sh),9.92, 10.25 and 10.95 (broad) μ; [α]_(D) ²⁰ =-153°±1° (c=0.916%, inCHCl₃).

EXAMPLE 100: 2-[(4R)-4-Acetylthio-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester

(a) A solution of 4.6 g of2-[(4R)-4-benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester in 120 ml of dimethylformamide is cooled to -20°, asolution of 670 mg of sodium borohydride in 80 ml of dimethylformamideis added and the mixture is stirred for 10 minutes at the sametemperature. The temperature of the reaction mixture is increased to 0°for 60 minutes, then cooled again to -20°, whereupon 40 ml of freshlydistilled acetyl bromide are added dropwise and the mixture is furtherstirred at 0° for 2 hours. After adding 1.5 l of benzene, the reactionmixture is washed in succession with ice water, water, 8% aqueous sodiumbicarbonate solution and water, dried over sodium sulphate andconcentrated in vacuo. After chromatography over silica gel (deactivatedwith 10% water) with toluene and toluene/ethyl acetate (19:1), theresidue yields the title compound which is slightly contaminated by the(4S)-enantiomer. Repeated chromatography and recrystallisation fromdiethyl ether/pentane yields the pure title compound having a meltingpoint of 81°-82°; [α]_(D) ²⁰ =+149°±1° (c=0.994%, CHCl₃);

TLC: R_(f) =0.40 (ethyl acetate/toluene 1:1); IR spectrum (in methylenechloride): absorption bands at 3.35-3.57, 5.66, 5.81, 5.89, 5.96 (sh),6.15, 7.00, 7.07 (sh), 7.25, 7.35, 7.72, 8.15, 8.22 (sh), 8.35 (sh),8.86, 9.15, 9.26, 9.42, 9.95, 10.11, 10.50 (broad) and 10.80μ.

(b) The partial racemisation can be prevented by the following method ofoperation:

1 g of zinc powder is added in portions over a period of one hour to asolution, stirred under nitrogen and in an ice bath, of 380 mg (1 mmol)of2-[(4R)-4-(benzthiazol-2-yl-dithio)-2-oxoazetindin-1-yl]-3-methylcrotonicacid methyl ester in 3 ml of acetic anhydride and 5 ml of glacial aceticacid. The reaction mixture is further stirred for one hour at roomtemperature, filtered and concentrated in vacuo. The residue is taken upin methylene chloride and washed in succession with 25% aqueous ammoniumchloride solution and aqueous sodium bicarbonate solution. The combinedaqueous phases are reextracted with methylene chloride, all themethylene chloride phases are combined, dried with sodium sulphate andconcentrated in vacuo. The residue is chromatographed over 40 g ofsilica gel (deactivated with 10% water) with toluene and toluene/ethylacetate (19:1) and yields the optically pure title compound having amelting point of 78°-80°;

[α]_(D) ²⁰ =+149°±1° (c=1.007%; in CDCl₃).

EXAMPLE 101 2-[(4R)-4-Acetylthio-2-oxoazetidin-1-yl]-2-oxoacetic acidmethyl ester

4 equivalents of ozone are introduced over a period of 60 minutes into asolution, cooled to -15°, of 150 mg of2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-3-methylcrotonic acid methylester in 3 ml of methanol. The reaction mixture is rinsed with nitrogen,diluted with methylene chloride and washed for 2 minutes with a 5%aqueous sodium bisulphite solution. The organic phase is dried oversodium sulphate and concentrated in vacuo. IR spectrum of the resultingoily title compound (in methylene chloride): characteristic bands at3.30-3.40, 5.52, 5.70, 5.83 (sh), 5.86, 6.98, 7.08 (sh), 7.40, 7.82-8.00(broad, sh), 8.07, 8.19, 8.30 (sh), 8.46, 8.90, 9.22, 9.52, 9.91, 10.30and 10.73μ. The product obtained can be used in the next stage withoutfurther purification.

EXAMPLE 102 (4R)-4-Acetylthio-2-oxoazetidine

A solution of 140 mg of2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-oxoacetic acid methyl ester(crude product) in a mixture of 20 ml of methanol, 2 ml of methylacetate and 0.4 ml of water is allowed to stand for 20 hours at roomtemperature, concentrated in vacuo and evaporated again with benzene.The residue is chromatographed over silica gel thick layer plates withtoluene/ethyl acetate (2:1) and yields the title compound.

TLC: R_(f) =0.20 (ethyl acetate/toluene 1:1); IR spectrum (in methylenechloride): characteristic absorption bands at 2.98, 5.62, 5.91, 7.13,7.41 (sh), 7.46, 7.83-8.15 (broad), 8.62, 8.89, 9.07 (sh), 9.20 (sh),10.19, 10.58 and 11.05-11.15 (broad) μ; [α]_(D) ²⁰ =+359°±1° (c=0.947%,in CHCl₃).

EXAMPLE 103 2-[(4R)-4-Acetylthio-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester

200 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 2 g ofmolecular sieves A4 are added to a solution of 54.5 mg of(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 4 ml oftoluene and 1 ml of dimethylformamide, and the mixture is stirred for 2hours at 50°. The molecular sieves are filtered off and the filtrate isconcentrated in vacuo. The residue is chromatographed over silica gel,and by elution with toluene/ethyl acetate (9:1) the title compound,contaminated with some glyoxylate, is obtained.

TLC: R_(f) =0.48 (ethyl acetate); IR spectrum (in CH₂ Cl₂): absorptionbands at 2.89 (broad), 5.64, 5.73, 5.91, 6.24, 6.56, 7.44, 7.62,7.83-8.15 (broad, sh), 8.26, 8.39 and 8.80-9.30 (broad) μ.

EXAMPLE 1042-[(4R)-4-Acetylthio-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 2.86 g (˜24 mmol) of thionyl chloride in 20 ml ofdioxan is added dropwise to a suspension, stirred at room temperature,of 12 g of poly-Hunig base in a solution of 2.83 g (7.59 mmol) of2-[(4R)-acetylthio-2-oxoazetidin-1-yl]-2-hydroxyacetic acidp-nitrobenzyl ester in 100 ml of dioxan. The mixture is stirred for 1.5hours at room temperature and filtered off from the poly-Hunig base,which is subsequently washed with dioxan. The filtrate is concentratedin vacuo. The 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester obtained is used in the next stage in crudeform.

(b) 3.144 g (˜1.5 equivalents) of triphenylphosphine and 12 g ofpoly-Hunig base are added to a solution of 3.1 g of2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroacetic acidp-nitrobenzyl ester in 120 ml of dioxan and the mixture is stirred for17 hours at 50° under nitrogen. The poly-Hunig base is filtered off,washed with dioxan and the filtrate concentrated in vacuo. The residueis chromatographed twice over silica gel with toluene and toluene/ethylacetate (4:1 and 3:2) and yields the title compound.

TLC: R_(f) =0.21 (ethyl acetate/toluene 1:1); IR spectrum (in methylenechloride): characteristic absorption bands at 3.30-3.55, 5.70, 5.90,6.05 (sh), 6.09 (sh), 6.16, 6.22 (sh), 6.57, 6.74, 6.96, 7.05 (sh),7.20, 7.44, 7.80-8.05 (broad), 8.25, 8.40, 8.85, 9.05 and 9.25μ; [α]_(D)²⁰ =+35°±1° (c=1.061% in CHCl₃).

EXAMPLE 105 (5R)-2-Methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 500 mg of(4R)-2-[4-acetylthio-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticp-nitrobenzyl ester in 500 ml of absolute toluene and the mixture isstirred for 40 hours at 90° under argon. The toluene is evaporated offin vacuo and the residue is chromatographed over 20 g of silica gel withtoluene/ethyl acetate (19:1). The title compound is obtained incrystalline form.

Melting point: 147.5°-149.5° (from methylene chloride/diethyl ether);

TLC: R_(f) =0.54 (ethyl acetate/toluene 1:1); [α]_(D) ²⁰ =+136°±1°(c=1.034%, in CHCl₃); IR spectrum: absorption bands at 3.40-3.55, 5.59,5.84, 5.95 (sh), 6.22 (sh), 6.30, 6.55, 7.15, 7.28, 7.41, 7.61, 7.69(sh), 8.28, 8.35, 8.56, 8.63 (sh), 9.02 (sh), 9.10, 9.25, 9.43, 9.62 and9.84μ.

EXAMPLE 106 (5R)-2-Methyl-2-penem-3-carboxylic acid

140 mg of 10% palladium/carbon catalyst are added to a solution of 100mg of (5R)-2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in amixture of 6 ml of ethyl acetate and 4 ml of 0.2M sodium bicarbonatesolution, and the mixture is hydrogenated for 30 minutes at roomtemperature under atmospheric pressure. After adding a further 70 mg ofcatalyst, hydrogenation is effected again for 30 minutes. Thehydrogenated mixture is filtered through diatomaceous earth; the filterresidue is washed with 2 ml of 0.2M aqueous sodium bicarbonate solutionand methyl acetate. The aqueous phase is separated from the filtrate,washed with methylene chloride, acidified with 5% aqueous citric acidand extracted several times with methylene chloride. The combinedmethylene chloride extracts are dried over sodium sulphate, concentratedin vacuo and recrystallised from acetone -20°.

Melting point: 142°-145° (with decomposition); [α]_(D) ²⁰ =+286°±1°(c=0.603%, in acetone; (IR spectrum (in KBr): absorption bands at2.85-4.30 (broad), 5.60 (sh), 5.66, 5.97 (sh), 6.04, 6.42, 6.50 (sh),7.05 (broad), 7.32, 7.64 (broad), 7.80 (broad), 8.17-8.25 (broad) and8.40μ;

NMR spectrum (in d6-acetone/100 Mc, in ppm): 2.31, 3H, s; 3.39, 1H, dd,J₁ =16 Hz, J₂ =2 Hz; 3.82, 1H, dd, J₁ =16 Hz, J₃ =4 Hz; 5.69, 1H, dd, J₂=2 Hz, J₃ =4 Hz.

EXAMPLE 107 (4R,S)-4-(Nicotinoylthio)-2-oxoazetidine

A solution of 6.95 g of thionicotinic acid in 50 ml of 1N sodiumhydroxide solution is added dropwise at room temperature under nitrogento a solution of 5.16 g of (4R,S)-4-acetoxyazetidin-2-one in 30 ml ofwater (a small excess of sodium hydroxide solution is added to maintainthe solution close to a pH of 8) and the mixture is stirred at the sametemperature for 1 hour. The reaction mixture is exhaustively extractedwith methylene chloride. The combined organic phases are dried oversodium sulphate and concentrated in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (2:3) andyields the title compound having a melting point of 112°-113°.

TLC: R_(f) =0.14 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 5.6, 5.97, 6.27, 8.15, 8.2, 10.85 and 11.12μ.

EXAMPLE 1082-[(4R,S)-4-(Nicotinoylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester

A solution of 3 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl esterin 60 ml of dry toluene and 15 ml of dry dimethylformamide is added atroom temperature to 1 g (4.8 mmol) of(4R,S)-4-(nicotinoylthio)-2-oxoacetidine. After adding freshly driedmolecular sieves, the mixture is stirred under nitrogen for 15 hours atroom temperature and then for 2 hours at 50°. The molecular sieves arefiltered off, washed with toluene and the filtrate and washing liquidare concentrated together in vacuo. The residue is chromatographed over200 g of silica gel with toluene/ethyl acetate (9:1 to 6:4). Aftereluting the unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester,the tital compound having the following physico-chemical properties iseluted:

TLC: R_(f) =0.13 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.62, 5.7, 6.0, 6.55, 7.4 and 8.22μ.

EXAMPLE 1092-[(4R,S)-4-Nicotinoylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A solution of 3.6 g (8.64 mmol) of2-[(4R,S)-4-(nicotinoylthio)-2-oxo-1-acetidinyl]-2-hydroxyacetic acidp-nitrobenzyl ester in 60 ml of absolute dioxan is added to a solutionof 13 g of poly-Hunig base in 30 ml of absolute dioxan that has alreadybeen stirred for 30 minutes. After adding a solution of 2.5 ml ofthionyl chloride in 24 ml of absolute dioxan, the reaction mixture isstirred for one hour at room temperature under nitrogen. The poly-Hunigbase is filtered off, washed with dioxan andd the filtrate and washingliquid are concentrated together in vacuo.

(b) The crude2-[(4R,S)-4-(nicotinoylthio)-2-oxo-1-azetidinyl]-2-chloroacetic acidp-nitrobenzyl ester obtained is dissolved in 150 ml of abxolute dioxanand stirred overnight at 50° under nitrogen with 12.9 g of poly-Hunigbase and 4.5 g of triphenylphosphine. The poly-Hunig base is filteredoff, washed with dioxan and the filtrate and washing liquid areconcentrated together in vacuo. The residue is chromatographed over 150g of silica gel with toluene/ethyl acetate (8:2 to 6:4) and yields thetitle compound with the following physico-chemical properties:

TLC: R_(f) =0.1 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.67, 6.0, 6.15, 6.55, 6.95, 7.4, 8.2, 9.05 and9.25μ.

EXAMPLE 110 (5R,S)-2-Pyrid-3-yl-2-penem-3-carboxylic acid p-nitrobenzylester

A catalytic amount of hydroquinone is added to a solution of 2.15 g of2-[(4R,S)-4-(nicotinoylthio)-2-oxo-1-azetidinyl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 1 l of absolute toluene and the mixture isstirred for 24 hours at 90° under nitrogen. The solvent is evaporatedoff in vacuo and the residue is chromatographed over 100 g of silica gelwith toluene/ethyl acetate (3:2). The title compound is obtained in theform of yellowish crystals having the following physico-chemicalproperties:

melting point: 160°-161° (diethyl ether/methylene chloride);

TLC: R_(f) =0.21 (toluene/ethyl acetate 2:3); UV spectrum (in ethanol):λ_(max) =333 nm (ε=6678); 259 nm (ε=15526);

IR spectrum (CH₂ Cl₂): absorption bands at 5.55, 5.78, 6.55, 7.4, 7.6,8.35 and 8.5μ; NMR spectrum in CDCl₃ /100 Mc, in ppm): 8.7-8.6, 2H, m;8.16, 2H, m; 7.78, 1H, m; 7.5-7.25, 3H, m; 5.84, 1H, m; 5.24, 2H, m;4.04-3.5, 2H, m.

EXAMPLE 111 (5R,S)-2-Pyrid-3-yl-2-penem-3-carboxylic acid

2 ml of water and 100 mg of 10% palladium/carbon catalyst are added to asolution of 50 mg (0.13 mmol) of(5R,S)-2-pyrid-3-yl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 3ml of absolute ethyl acetate and the mixture is stirred at normalpressure for 50 minutes under hydrogen. The hydrogenated mixture isfiltered off from the catalyst over diatomaceous earth and the filtrateis washed with water, ethyl acetate and again with water. The combinedaqueous phases are subjected to freeze-drying. The totle compoundobtained has the following physico-chemical properties:

UV spectrum (in ethanol): λ_(max) =316 nm; IR spectrum (KBr): absorptionbands at 7.9, 1H, m; 7.6, 1H, m; 2.95, 5.65, 6.2 and 7.3μ.

EXAMPLE 112

In an analogous manner and using suitable intermediate products,optionally with the release of functional groups, the followingcompounds may be obtained:

(5R,S)-2-Methyl-2-penem-4-carboxylic acid tert.-butyl ester;

TLC: R_(f) =0.63 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 3.9, 5.6, 5.85, 6.25, 7.3, 7.55 and 8.65μ.

(5R,S)-2-ethyl-2-penem-3-carboxylic acid;

(5R,S)-2-isopropyl-2-penem-3-carboxylic acid;

(5R,S)-2-hydroxymethyl-2-penem-4-carboxylic acid;

(5R,S)-2-acetoxyethyl-2-penem-3-carboxylic acid; and

(5R,S)-2-hydroxyethyl-2-penem-3-carboxylic acid,

as well as the corresponding (5R)- and (5S)-compounds; and their salts.

EXAMPLE 113

Dry ampoules or vials, containing 0.5 g of the sodium salt of(5R,S)-2-methyl-2-penem-3-carboxylic acid, are produced as follows:

    ______________________________________                                        Composition (for 1 ampoule or vial).                                          ______________________________________                                        Sodium salt of (5R,S)--2-methyl-2-penem-3-carboxlyic acid                                                  0.5 g                                            Mannitol                     0.05 g                                           ______________________________________                                    

A sterile aqueous solution of the sodium salt of(5R,S)-2-methyl-2-penem-3-carboxylic acid and of the mannitol issubjected to freeze-drying under aseptic conditions in 5 ml ampoules or5 ml vials and the ampoules or vials are sealed and examined.

EXAMPLE 114

Capsules, containing 0.25 g of (5R,S)-2-methyl-2-penem-3-carboxylicacid, are produced as follows:

    ______________________________________                                        Composition (for 1000 capsules)                                               ______________________________________                                        (5R,S)--2-methyl-2-penem-3-carboxlyic acid                                                            250,000 g                                             corn starch             50,000 g                                              polyvinylpyrrolidone    15,000 g                                              magnesium stearate      5,000 g                                               ethanol                 q.s.                                                  ______________________________________                                    

The (5R,S)-2-methyl-2-penem-3-carboxylic acid and the corn starch aremixed and moistened with a solution of the polyvinylpyrrolidone in 50 qof ethanol. The moist composition is pressed through a sieve having amesh width of 3 mm and dried at 45°. The dry granulate is forced througha sieve having a mesh width of 1 mm and mixed with 5 g of magnesiumstearate. The mixture is introduced into push-fit capsules, size 0, inportions of 0.320 g.

What is claimed is:
 1. Compounds of the formula ##STR10## in which Z'represents oxygen, sulphur or a methylidene group optionally substitutedby one or two substituents selected from the group consisting of loweralkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyland esterified carboxy, R₁ represents hydrogen, lower alkyl optionallymono-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen,lower alkylthio, carbamoyl, cyano, nitro, amino optionally mono- ordi-substituted by lower alkyl, lower alkyleneamino or amino acylated byacetyl, tert.-butoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl or phenoxyacetyl; protected carboxyl;aminocarbonyl optionally mono- or di-substituted by lower alkyl;cycloalkyl; cycloalkyl-lower alkyl; phenyl; naphthyl; phenyl-loweralkyl; phenyl, naphthyl or phenyl-lower alkyl mono-substituted by loweralkyl, lower alkoxy, halogen, nitro, amino or di-lower alkylamino;pyridyl; thienyl; furyl; pyridyl-lower alkyl; thienyl-lower alkyl;furyl-lower alkyl; lower alkylthio; lower alkenylthio; cycloalkylthio;cycloalkyl-lower alkylthio; phenylthio; phenyl-lower alkylthio; orlower-alkylthio, lower alkenylthio, cycloalkylthio, cycloalkyl-loweralkylthio, phenylthio or phenyl-lower alkylthio mono-substituted byhydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkylthio,carbamoyl, cyano, nitro, amino optionally mono- or disubstituted bylower alkyl, lower alkanoylamino or lower alkyleneamino; and R^(A) ₂together with the carbonyl group --C(═O)-- to which it is attachedrepresents a protected carboxyl group.
 2. Compound of the formula##STR11## in which Z' represents oxygen, sulphur or a methylidene groupoptionally substituted by one or two substituents selected from thegroup consisting of lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,phenyl, phenyl-lower alkyl and esterified carboxy, R₁ representshydrogen, lower alkyl optionally mono-substituted by hydroxy, loweralkoxy, lower alkanoyloxy, halogen, lower alkylthio, carbamoyl, cyano,nitro, amino optionally mono or di-substituted by lower alkyl, loweralkylene-amino or amino acylated by acetyl, tert.-butoxycarbonyl,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or phenoxyacetyl; protectedcarboxyl; aminocarbonyl optionally mono- or di-substituted by loweralkyl; cycloalkyl; cycloalkyl-lower alkyl; phenyl; naphthyl;phenyl-lower alkyl mono-substituted by lower alkyl, lower alkoxy,halogen, nitro, amino or di-lower alkylamino; pyridyl; thienyl; furyl;pyridyl-lower alkyl; thienyl-lower alkyl; furyl-lower alkyl; loweralkylthio; lower alkenylthio; cycloalkylthio; cycloalkyl-loweralkylthio; phenylthio; phenyl-lower alkylthio; or lower-alkylthio, loweralkenylthio, cycloakylthio, cycloalkyl-lower alkylthio, phenylthioorphenyl-lower alkylthio mono-substituted by hydroxy, lower alkoxy,lower alkanoyloxy, halogen, lower alkylthio, carbamoyl, cyano, nitro,amino optionally mono- or disubstituted by lower alkyl, loweralkanoylamino or lower alkyleneamino; and R^(A) ₂ together with thecarbonyl group --C(--O)-- to which it is attached represents a protectedcarboxyl group.